US5096807A - Imaging immunoassay detection system with background compensation and its use - Google Patents

Imaging immunoassay detection system with background compensation and its use Download PDF

Info

Publication number
US5096807A
US5096807A US07/449,502 US44950289A US5096807A US 5096807 A US5096807 A US 5096807A US 44950289 A US44950289 A US 44950289A US 5096807 A US5096807 A US 5096807A
Authority
US
United States
Prior art keywords
reactant
sample
samples
photons
photon
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US07/449,502
Inventor
David H. Leaback
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Murex Corp
Original Assignee
Murex Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB858505822A external-priority patent/GB8505822D0/en
Priority claimed from GB858512041A external-priority patent/GB8512041D0/en
Priority claimed from GB858517042A external-priority patent/GB8517042D0/en
Application filed by Murex Corp filed Critical Murex Corp
Application granted granted Critical
Publication of US5096807A publication Critical patent/US5096807A/en
Assigned to DX COMPANY, LTD. reassignment DX COMPANY, LTD. ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: LEABACK, DAVID H.
Assigned to INTERNATIONAL MUREX TECHNOLOGIES CORPORATION reassignment INTERNATIONAL MUREX TECHNOLOGIES CORPORATION SECURITY INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MUREX CORPORATION
Assigned to MUREX CORPORATION reassignment MUREX CORPORATION EXCHANGE AND ASSIGNMENT OF INTERESTS Assignors: DX COMPANY LTD.
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/76Chemiluminescence; Bioluminescence
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/531Production of immunochemical test materials
    • G01N33/532Production of labelled immunochemicals
    • G01N33/535Production of labelled immunochemicals with enzyme label or co-enzymes, co-factors, enzyme inhibitors or enzyme substrates
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/536Immunoassay; Biospecific binding assay; Materials therefor with immune complex formed in liquid phase
    • G01N33/542Immunoassay; Biospecific binding assay; Materials therefor with immune complex formed in liquid phase with steric inhibition or signal modification, e.g. fluorescent quenching
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366Apparatus specially adapted for solid-phase testing
    • G01N33/54373Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583Features relative to the processes being carried out
    • B01J2219/00603Making arrays on substantially continuous surfaces
    • B01J2219/00605Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583Features relative to the processes being carried out
    • B01J2219/00603Making arrays on substantially continuous surfaces
    • B01J2219/00605Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • B01J2219/00612Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports the surface being inorganic
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583Features relative to the processes being carried out
    • B01J2219/00603Making arrays on substantially continuous surfaces
    • B01J2219/00605Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • B01J2219/00614Delimitation of the attachment areas
    • B01J2219/00617Delimitation of the attachment areas by chemical means
    • B01J2219/00619Delimitation of the attachment areas by chemical means using hydrophilic or hydrophobic regions
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583Features relative to the processes being carried out
    • B01J2219/00603Making arrays on substantially continuous surfaces
    • B01J2219/00605Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
    • B01J2219/00623Immobilisation or binding
    • B01J2219/00626Covalent
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583Features relative to the processes being carried out
    • B01J2219/00603Making arrays on substantially continuous surfaces
    • B01J2219/00659Two-dimensional arrays
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/0068Means for controlling the apparatus of the process
    • B01J2219/00702Processes involving means for analysing and characterising the products
    • B01J2219/00707Processes involving means for analysing and characterising the products separated from the reactor apparatus
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2201/00Features of devices classified in G01N21/00
    • G01N2201/04Batch operation; multisample devices
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00Chemistry: molecular biology and microbiology
    • Y10S435/965Chemistry: molecular biology and microbiology involving idiotype or anti-idiotype antibody
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00Chemistry: molecular biology and microbiology
    • Y10S435/973Simultaneous determination of more than one analyte

Definitions

  • This invention relates to an imaging immunoassay detection system and method.
  • Another prevalent technique is the colorimetric enzyme immunoassay which utilises enzymes as labels.
  • An enzyme-linked immunoreactant binds either to an antigen or to an antibody, causing a reaction which yields a quantitative measure of the antibody or antigen, which can be detected by a colour change.
  • Such an assay is usually slower than other conventional techniques involving automated assays.
  • a third method that can be used is a fluorescence immunoassay, based on the labelling of an antigen or antibody with fluorescent probes.
  • U.S. Pat. No. 4320970 discloses a photon-counting fluorimeter that may be used in such an assay. Disadvantages of such a system include the necessity of processing only one sample at a time. Other systems attempt to use laser beams as the external light source to excite the solution, as disclosed in U.S. Pat. No. 3984533. Again, this system can process only one sample at a time.
  • Instrumentation for luminescence assays advantageously involves a self-exciting luminescing system, in direct contrast to fluorimeters which utilise an external light source.
  • existing luminometers are complex in operation and require the use of substantial quantities of the reagent being sampled.
  • a microprocessor was used to control fluid and air valves for adding the desired chemicals to each well; the carrier was moved in an x-y plan, to position the individual wells sequentially over a phototube, in order to enable the photons emitted by the reaction to be counted. The results were displayed by a printer. Even though photons were counted for 2 seconds at 10 second intervals, obviously a great deal of time would be required to analyse hundreds or thousands of test specimens in sequential order, one at a time.
  • GB-A-2132347 discloses a chemiluminometer for simultaneously handling multiple samples. The results obtained, however, are only semi-quantitative.
  • the terms “luminescent” and “luminescence” mean all kinds of light emission except incandescence and include chemiluminescence, bioluminescence, prompt fluorescence, delayed fluorescence and phosphorescence and the like.
  • the present invention overcomes the given drawbacks and provides an imaging immunoassay detection apparatus system and method capable of detecting and quantifying multiple light-emitting reactions from small volume samples simultaneously.
  • the present invention is very advantageous inasmuch as it is very rapid because it analyses all samples simultaneously, is extremely accurate because it requires no mechanical motion of components, has no repositioning errors as in sequential resolution, can use an internal standard such as a known sample to obtain comparative information, is adaptable with a filter to handle any particular wavelength of light, and is versatile in that it can detect assays requiring external light as well as those that do not require external light, thus being able to operate with immunoassays utilising luminescence and fluorescence and the like.
  • the present invention comprises an imaging system for detecting photons generated by chemical reactions
  • sample carrier means having a plurality of individual areas each containing individual chemical reactant samples capable of emitting photons if a reaction takes place, the plurality of reactant-containing areas being arranged in spaced relationship with respect to each other; imaging means associated with said carrier means for simultaneously receiving individual photons emitted from each area sample where a reaction is taking place; and means coupled to the photon-receiving imaging means for generating a signal representing the x-y location of each area sample generating a photon, whereby the reactants in each area sample having a reaction and the number of its photon emissions over any predetermined period of time may be simultaneously identified.
  • the invention also comprises a method of simultaneously detecting photons generated by a plurality of chemical reactions, comprising the steps of providing a plurality of individual chemical reactant samples each capable of emitting photons when a reaction takes place, the samples being arranged in spaced relationship with respect to each other, and simultaneously detecting the presence and x-y location of each photon emitted from any reacting samples, whereby the total number of photons emitted from each reacting sample over a predetermined period of time may be determined.
  • the present invention is not only extremely rapid and processes simultaneously multiple assays, but also enables considerable economies to be made in the use of often expensive reagents concerned because only small quantities of samples are required.
  • FIG. 1 is a diagrammatic representation of the novel photon detection system
  • FIG. 2 is a diagrammatic representation of the imaging photon detector used in the system of FIG. 1;
  • FIG. 3 is a representation of both background noise signals and signals from discrete areas of reaction (whereby the background noise signals may be cancelled, leaving only reaction signals);
  • FIG. 4 represents a carrier in which multiple antibody labels may be used simultaneously or in which a standard reaction may be compared with other reactions;
  • FIG. 5 is a diagrammatic representation of how a wavelength interference filter may be used with the carrier of FIG. 4 to pass only a particular light wavelength, thereby allowing only photons of a particular wavelength corresponding to a labelled antibody to pass to the imaging detector;
  • FIG. 6 is a schematic representation of a circuit in a microprocessor for subtracting background noise from the sample signals to obtain an output signal representing substantially only pure photon emission from a reactant sample;
  • FIG. 7 is a diagrammatic representation of the use of invisible ultraviolet radiation as a source of external light.
  • the apparatus of the present invention may be utilised with any number of different assay techniques as stated earlier, but will be described with particular reference to the use of luminescent immunoassays in the detection of antigen-antibody reactions. More particularly, the invention can be employed to detect the characteristic reactions of labelled monoclonal and polyclonal antibodies with antigens found in samples such as urine, faeces, blood, milk and water and the like.
  • Monoclonal antibodies may be prepared by the technique first described by Kohler and Milstein, Eur. J. Immunol. 6, 292 (1975).
  • the monoclonal antibodies may be labelled with a multitude of different labels, such as luminescent or fluorescent compounds.
  • the particular labels utilised in the present invention must be capable of emitting light once the antigen-antibody reaction occurs, and thus the reactions are designated as "light-emitting reactions".
  • the present invention will be described in general with reference to a luminescent-labelled monoclonal antibody, although fluorescent labels may also be used as disclosed hereafter.
  • the term "reactants” means the combination of (1) a monoclonal antibody labelled with a luminescent or fluorescent compound, and (2) an antigen.
  • Luminescence is the emission of light by an atom or molecule as an electron is transferred to the ground state from a higher energy state.
  • the free energy of a chemical reaction provides the energy required to produce an intermediate reaction or product in an electronically excited state. Subsequent decay back to the ground state is accompanied by emission of light.
  • Bioluminescence is the name given to a special form of chemiluminescence found in biological systems such as the firefly, in which a catalytic protein or enzyme, such as luciferase, increases the efficiency of the luminescent reaction.
  • luciferase When this luciferase enzyme is combined with its substrate, luciferin, in the presence of ATP (adenosine triphosphate), magnesium and oxygen, a flash of light is produced, whose intensity is proportional to the amount of ATP present in the sample.
  • ATP adenosine triphosphate
  • the firefly luciferase/luciferin/ATP system is as follows: ##STR1## where h ⁇ is the energy of a photon, h is the Planck constant, and ⁇ is the frequency associated with the photon.
  • Assays of the invention can directly determine the number of live organisms in a sample, either because the presence of ATP in a test sample indicated live cells, or because of the presence of immunoglobulins labelled with a luminescence-detectable enzyme (like peroxidase or luciferase).
  • Chemiluminescent substances such as luminol may also be utilised in a horseradish peroxidase-catalysed oxidation, as follows: ##STR2##
  • the "light-emitting reactions" generate photons which are coupled to an imaging device such as an imaging photon detector, a charge-coupled device, or a vidicon tube (any of a variety of camera tubes having a photoconductive target).
  • an imaging photon detector is used.
  • the reactions may be generated by reactants spatially arranged in individual areas on a sample carrier in a single row or column or by a two-dimensional array of reactants spatially arranged, for instance, in rows and columns.
  • a carrier may have an array, such as rows, of 1 mm outside diameter nylon tubes containing the labelled monoclonal antibodies, to which is added the specimen or specimens being tested for the presence of an antigen.
  • the fluids involved are self-contained and of a very small volume.
  • an advantage of the present invention is that the imaging photon detector can quantify (in 10 seconds or less) light emitted from multiple "light-emitting reactions", in volumes of 3 ⁇ l or less, i.e. much smaller than can be used in known apparatus.
  • Another carrier suitable for use with an imaging photon detector is a microtiter plate with multiple samples in rows and columns.
  • a particular plate may contain as many as 96 individual wells. Each well contains different labelled monoclonal antibodies adsorbed on the surface of the plate. A portion of the specimen is added to each well. The presence and quantity of a particular antigen in an individual well is determined by the number of photons generated by the antigen-antibody reaction.
  • a third carrier involves the principle of using immobilised antibodies on a plurality of filaments; labelled monoclonal antibodies are immobilised in individual areas on a plurality of filaments. Each filament may bear a different labelled monoclonal antibody capable of emitting light upon the detection of an antigen. Because the reactions on the individual filaments generate light, the imaging photon detection system can quantitatively determine the presence of particular antigens.
  • the present invention envisages the use of any number of different types of multiple, chemically-produced, light-emitting reactions which can be imaged by the image photon detector. As the samples emit light, the present invention counts the individual photons impinging upon a light sensitive photocathode of an imaging photon detector.
  • Each of the above means for containing a plurality of reactants can be used in the apparatus system described below, in which the container is identified as the specimen carrier means.
  • FIG. 1 is a system for quantitative assay analysis of multiple biochemical images using an imaging photon detector.
  • the system enables the detection of very low concentrations of substances present in fluid samples or specimens which, in the course of their reaction, emit light photons under certain conditions.
  • the system has demonstrated sensitivity in the order of 10 -16 and lower.
  • FIG. 1 shows a specimen carrier means 10 which may include a plurality of fluid samples all capable of simultaneously undergoing a reaction. Samples can be spaced in individual areas as a row or column or in a two-dimensional array of rows and columns as shown in FIG. 3 and FIG. 4, for example only.
  • the reactions that produce light generate photons 12 which are focused by an optical system 14 to form the image of the light outputs of each of the samples on a photoconductive target forming a portion of an imaging photon detector (IPD) 16.
  • IPD imaging photon detector
  • the imaging photon detector 16 will be disclosed in detail hereinafter but is known in the art; it immediately converts incoming light into quantitative information which can be stored and processed within a memory of any conventional computing means such as a microprocessor 24.
  • the imaging detector 16 of the present invention takes simultaneous readings of discrete sample areas such as the small darker shaded orthogonal areas of FIG. 3 rather than averaging the readings of the entire sample area (including the carrier area surrounding the sample).
  • Background noise represented by the shading lines in FIG. 3, is caused by non-specific binding antigens or antibodies to the solid surface of the carrier, which are not washed away in the preparation of the carrier.
  • Conventional detectors read these signals generated by this undesirable binding and, because these conventional detectors average the signal over the entire sample area, they interpret these undesired false signals as a positive reaction. Background noise effectively decreases the sensitivity of the assay at relatively low levels of concentration, where the positive reaction signal has nearly the same intensity level as the background noise.
  • the present invention eliminates the background noise problem by simultaneously reading the signal from the background environment and the signal from the concentrated reaction area and comparing the two readings. Because the present imaging immunoassay detection system can read signals from numerous discrete reaction areas at the same instant, a real time measurement of the signals from the discrete areas of reaction in a two-dimensional array can be taken, averaged, and compared with the signal representing the background noise caused by the non-specific binding. The computer 24 can analyse and display the results by subtracting from the signals representing the discrete areas of reactions the signals representing the background noise, as shown in FIG. 6, thereby leaving the pure reaction signals.
  • the present system can simultaneously evaluate a carrier, such as a 96-well microtiter tray, without repositioning the carrier or tray as in systems using sequential detection, resolution errors that occur from imprecise mechanical repositioning of the samples between measurements as required in the prior art are eliminated.
  • a carrier such as a 96-well microtiter tray
  • the present imaging immunoassay detection system can look at more than one discrete reaction at a time, contrasting reactions can be analysed relative to one another.
  • a two-dimensional array of samples as in a microtiter tray represented in FIG. 4 reactions can be compared side-by-side simultaneously.
  • the amount of photons generated by each reaction can be read and analysed by computer 24 and the relative extent of reaction compared. In this way, a more accurate comparison can be made between specific samples, thus providing better test results.
  • a negative reaction may be placed in a discrete area A in FIG. 4, to serve as a control for purposes of comparison with a positive reaction in a discrete area B.
  • the negative reaction in discrete area A may still generate spurious signals caused by non-specific binding, as pointed out earlier.
  • This background noise level is potentially constant across a given carrier such as a microtiter tray and is useful in setting up a base level of signal generation from which more positive reaction can be compared.
  • the present imaging system is capable of rapid quantitative analysis of samples. Because of its unique ability to simultaneously read and analyse numerous samples, the time necessary to produce results is dramatically reduced.
  • the sensitivity of the present imaging system allows for very accurate measurements even at very low concentrations of the samples.
  • an imaging photon detector is capable of measuring individual photons of light.
  • the system is able to register very low concentrations of materials and is therefore useful in areas such as diagnosing for the presence of infectious organisms, as well as drug monitoring and disease detection.
  • the imaging system can not only detect minute quantities of a reaction samples, but can also read a very small area of reaction. Thus, the amount of reagent and the area which are needed to conduct the assay are less then before, thereby minimising the cost of reagents and carrier materials.
  • the output of the imaging photon detector 16 on line 18 comprises analog signals which represents the x-y spatial correspondence of each detected photon, thus identifying electrically the x-y address of the sample or specimen that produced the light.
  • These analog signals are coupled to an analog-to-digital (A/D) converter 20 which produces digital output signals on lines 22 representing the spatial orientation of the specimen source producing the photon received by the imaging photon detector 16 and thus identifying the particular sample or specimen which produces the photon.
  • the digital signals 22 are coupled to a microprocessor 24 which stores and analyses the image information and can be programmed to display it in any desired format. The reactions continue to generate light throughout any desired predetermined period of time, e.g.
  • microprocessor 24 produces signals on line 26 to video display 28 and printer 30 for visual display and analysis of the light received, and accumulated, from samples 10.
  • a bar chart may be displayed on video terminal 28 which identifies each of the samples and illustrates the relative amount of light or number of photons being generated by each sample. Such a bar chart could also be produced, for a permanent record, by printer 30.
  • a two-dimensional image of the array of samples as they are physically located can be produced, the intensity of the light generated by each sample being indicated either in colour or by numerals, thus identifying which sample is generating the greatest amount of light.
  • the microprocessor 24 can perform any operation on the samples as desired to correct and calibrate the image and to compensate for any inherent noise in the system such as by subtracting the background noise, as explained earlier. Noise also may be reduced by cooling the imaging photon detector 16 with a cooling unit 15 in any well known manner such as by circulating a cooling liquid or a refrigerant about the imaging photon detector 16. Cooling the detector 16 reduces the tendency for free electrons to be emitted from elements of the detector 16, and which assist in generating the background noise.
  • FIG. 2 is a diagrammatic representation of the construction details of the imaging photon detector used in the preferred embodiment herein and which is known in the art.
  • the detector may be type IPDG1 or type PIDF1 manufactured by Instrument Technology Limited in East Canal, England.
  • the imaging photon detector 16 is a two-dimensional imaging sensor capable of detecting extremely weak radiation, e.g, capable of detecting an ATP content in the sample down to as low as 10 -16 moles/sample. As indicated earlier, that image is produced in analog form which is converted through an analog-to-digital converter 20 to a digital form for use by the microprocessor 24.
  • Light is composed of individual photons. Each individual photon has an extremely small amount of energy associated therewith. In most common images, the light contains fluxes of millions or billions of photons per square centimeter and per second. Using the imaging photon detector 16, each incoming photon has a high probability of detection by the photocathode 32.
  • the photoconductive target 32 can thus be thought of as equivalent to a photographic film except that it has a sensitivity of the order of 100 times greater.
  • a photoelectron is released from photocathode 32 and is immediately accelerated into a series of microchannel plate intensifiers or amplifiers 34.
  • a gain in the range of 3 ⁇ 10 6 to 3 ⁇ 10 7 electrons is emitted from the rear of each microchannel plate for each incident photoelectron and thus corresponds to each initially detected photon.
  • the combination of the microchannel plates 34 thus enables extremely small amounts of light to be detected.
  • a resistive anode encoder 36 located immediately behind the microchannel plates 34 translates the electron burst into signals which can be processed easily into a two-dimensional x-y address of the detected photon and thus the sample.
  • the analog readout of the resistive anode 36 on line 18 in FIG. 1 is used to present a linear x-y registration of each photoelectron event.
  • the read-out through four orthogonal electrodes 38 is suitably processed to provide digital representation of the x-y position of the incident photoelectron (and thus the sample) by analog-to-digital converter 20 and microprocessor 24, both shown in FIG. 1.
  • the imaging photodetector 16 detects and presents information relating to multiple imaging, presents the information immediately upon the occurrence of the emitted light, detects extremely small amounts of light down to and including a single photon, and quantifies such information for each specific x-y sample or specimen address.
  • the system may use a charge-coupled device (CCD) as the imaging device 16.
  • CCD charge-coupled device
  • CCD's are well known in the art. They are used in conjunction with an optical lensing system (such as optical system 14 in FIG. 1) which focuses light from the object being investigated (sample array 10 in FIG. 1) on to the CCD. Varying amounts of light from individual samples are incident on individual pixels within the CCD and charge the pixels to different levels proportional to the incident light. Thus the optical information or light from sample array 10 is available in analog form across the pixels of CCD array 16.
  • the analog information is then shifted out of the CCD and converted to digital form in a well known manner by the analog-to-digital converter 20 and is then coupled to a memory in computer 24 where the various measurement levels and comparisons can be made by appropriate manipulation of the digital information. See "Imaging”, The Optical Industry and System Purchasing Directory, 1983, pp. E-72 to E-74.
  • the individual pixels within a CCD array are closely spaced and arranged horizontally in rows and vertically in columns so that a given CCD imaging device 16 provides a fixed number of pixels of information. For instance, some CCD's have 320 vertical columns of pixels and 512 horizontal rows of pixels.
  • CCD's have several characteristics which make them advantageous in the present invention as an imaging device.
  • CCD's are small and rugged and have closely spaced pixels and are therefore useful where, as here, precise measurements are required. They also receive an image by the direct reception of light energy without being scanned, and store the received data until the data are transferred to another storage device. Further, the data received from the CCD can be processed by simple comparison or detection techniques, thereby avoiding complex and major time-consuming sampling techniques ordinarily used to process such data.
  • vidicon tube Another imaging device which can be used instead of an imaging photon detector or a CCD is a vidicon tube.
  • the name vidicon is generally applied to any of a variety of tubes having a photoconductive target.
  • the vidicon operates in a well known manner and utilises an electron beam to scan a light-sensitive photoconductive target.
  • a transparent conductive layer applied to the front side of the photoconductor serves as a signal or target electrode.
  • the target electrode is operated at a positive voltage with respect to the back side of the photoconductor which operates at cathode (near zero) voltage. In operation, the scanning beam initially charges the back side of the target electrode to cathode potential.
  • a vidicon 16 receives the photons or light output from the respective reactions through optics 14 and produces the analog output on line 18 as described earlier.
  • the analog output on line 18 is coupled to the analog-to-digital converter 20 from which digital signals are processed in the same manner as for the imaging photon detector.
  • each discrete area A may have an antibody labelled with an indicator such as luciferase
  • discrete area B may have an antibody labelled with an indicator such as a bacterial reductase, and so forth. Since each indicator generates a different wavelength of light, each discrete area of each antibody has its own particular wavelength of light which can be detected by imaging device 16. As can be seen in FIG.
  • a wavelength interference filter 40 of the desired characteristics is placed between samples 10 and optics 14 such that only photons of a particular wavelength corresponding to an antibody labelled with a particular indicator pass through to the imaging detector 16.
  • the novel imaging immunoassay detection system can be made wavelength selective, thereby permitting greater flexibility and sensitivity.
  • FIG. 7 illustrates such apparatus, wherein an ultraviolet light source 54 is powered by an appropriate power source 56.
  • Ultraviolet light rays 58 impinge on samples in carrier 10 which fluoresce if a reaction takes place. The remainder of the circuit operates as described above in connection with FIG. 1.
  • the signals detected by imaging device 16 representing background noise and sample signals combined, are stored in a memory 42 of microprocessor 24.
  • the detected signals representing background noise alone are stored in a memory 44 of microprocessor 16.
  • DNA probes or RNA probes are specific sequences of nucleotides that are complementary to particular sequences of a sample piece of DNA or RNA. These probe pieces of DNA or RNA can be labelled with an indicator so as to generate a signal, analogous to an immunoassay, and would be contained in a carrier 10 such as shown in FIG. 1.
  • the DNA or RNA is first removed from a cell or other structure in a sample containing a DNA or RNA sequence.
  • the DNA or RNA is bound to a surface such as nitrocellulose, and is then denatured so that its complementary strands are separated.
  • the DNA or RNA probe labelled with an indicator, is then added to the sample and, if the specific complementary sequence of the probe is present in the sample, the sample and probe will combine.
  • the unbound label is washed away and the sample containing bound labelled probe is read in the manner described hereinabove with reference to FIG. 1.
  • Isotope-labelled assays are also within the scope of the present invention.
  • the indicator component is labelled with an isotope, such as phosphorus-32 or iodine-125, which emits gamma radiation.
  • an isotope such as phosphorus-32 or iodine-125
  • the isotope-labelled component typically an antibody
  • the isotope-labelled component is bound to the analyte of interest, the unbound label is washed away from the reaction zone, and the zone is read.
  • the reading of the central reaction zone is accomplished in this embodiment by the incorporation of a phosphor screen.
  • Phosphor screens are well known in the art and are used to convert electron energy into radiant energy.
  • These screens are composed of a thin layer of luminescent crystals, phosphors, which emit light when bombarded by electrons.
  • the phosphor screen receives gamma radiation from the labelled analyte and, in turn, emits photons which are received by the detection system.
  • carrier 10 would be the phosphor screen which received electrons from any reaction and emits light 12 which is focused by optics 14 and processed in the manner explained previously. In this manner, gamma particles are converted into detectable photons which are received and processed as described hereinabove.
  • Other types of gamma-to-photon conversion means are also usable and within the scope of the present invention.
  • the well established firefly luciferase/luciferin-based assay for ATP provides a useful reference.
  • the lower limit for the assay (carried out as recommended by the manufacturer) is set by the "background" count of photons (of about 10/second) typically experienced. This sets the lower limit of the determination at about 5 ⁇ 10 -15 moles ATP per sample.
  • the lower limit of the determination is set at about 5 ⁇ 10 -17 moles ATP.
  • Monoclonal antibodies are prepared according to the method of Kohler and Milstein noted above.
  • an antibody to Shigella is prepared by the procedure described in WO-A-86/00296 and labelled with luminescent compounds such as the firefly luciferase/luciferin/ATP system.
  • luminescent labelled antibodies are then adsorbed onto the surface of a microtiter tray.
  • each well of the tray may contain labelled monoclonal antibodies to different antigens, thus allowing diagnosis for the presence of a wide variety of different antigens at the same time.
  • This microtiter tray thus contains a number of known antibodies at known x-y addresses or areas on the tray.
  • the tray is then washed with the specimen containing the unknown antigen(s) and an antigen-antibody reaction occurs. Next, the tray is rinsed and unbound antibodies are removed. Then, the tray is placed in the specimen carrier holder of the imaging photon detecting system described above. The presence and amount of the unknown antigen(s) in the specimen are determined by the photons generated by the characteristic antigen-antibody reactions and their x-y location on the microtiter tray.

Abstract

The invention provides an imaging immunoassay detection apparatus system and method capable of detecting multiple light emitting reactions from small volume samples simultaneously and quantifying the same.

Description

This is a continuation of application Ser. No. 835,992, filed Mar. 4, 1986, now abandoned.
This invention relates to an imaging immunoassay detection system and method.
BACKGROUND OF THE INVENTION
Highly sensitive instrumentation for immunoassay techniques has been developed to enable measurement of reactions of extremely small quantities of biological and chemical substances. For example, instruments for radioimmunoassay are used which are sensitive, accurate and precise, but require expensive gamma-counting equipment. Other disadvantages of such systems include the short half-life of the radioisotopes, and the danger of using and disposing of the radioactive compounds used in such assays.
Another prevalent technique is the colorimetric enzyme immunoassay which utilises enzymes as labels. An enzyme-linked immunoreactant binds either to an antigen or to an antibody, causing a reaction which yields a quantitative measure of the antibody or antigen, which can be detected by a colour change. Such an assay is usually slower than other conventional techniques involving automated assays.
A third method that can be used is a fluorescence immunoassay, based on the labelling of an antigen or antibody with fluorescent probes. U.S. Pat. No. 4320970 discloses a photon-counting fluorimeter that may be used in such an assay. Disadvantages of such a system include the necessity of processing only one sample at a time. Other systems attempt to use laser beams as the external light source to excite the solution, as disclosed in U.S. Pat. No. 3984533. Again, this system can process only one sample at a time.
Instrumentation for luminescence assays advantageously involves a self-exciting luminescing system, in direct contrast to fluorimeters which utilise an external light source. In general, existing luminometers are complex in operation and require the use of substantial quantities of the reagent being sampled.
Further efforts to analyse more than one reagent sample simultaneously, in a quantitative sense, have not been successful. Efforts toward this end are illustrated by a system described by Schroeder et al in "Immunochemiluminometric Assay for Hepatitis B Surface Antigen", Clinical Chemistry, Vol. 27 No. 8 (1981), wherein a carrier is prepared containing a plurality of reagents for analysis by a luminometer which measures light production during reaction by photo-counting. However, this method and apparatus have the disadvantage of requiring the reactions to be measured sequentially, one at a time. A microprocessor was used to control fluid and air valves for adding the desired chemicals to each well; the carrier was moved in an x-y plan, to position the individual wells sequentially over a phototube, in order to enable the photons emitted by the reaction to be counted. The results were displayed by a printer. Even though photons were counted for 2 seconds at 10 second intervals, obviously a great deal of time would be required to analyse hundreds or thousands of test specimens in sequential order, one at a time.
In addition, GB-A-2132347 discloses a chemiluminometer for simultaneously handling multiple samples. The results obtained, however, are only semi-quantitative.
It has heretofore not been possible to carry out luminescent assays on multiple, small volume samples simultaneously in a short period of time, i.e. seconds. Presently existing technology permits only one such assay at a time and often requires large volume samples, i.e. of 200 μl or more.
As used herein, the terms "luminescent" and "luminescence" mean all kinds of light emission except incandescence and include chemiluminescence, bioluminescence, prompt fluorescence, delayed fluorescence and phosphorescence and the like.
Rees et al, J. Phys. E: Sci. Instrum. 14 (1981) 229-233, describe a miniature imaging photon detector with a transparent photocathode. It is proposed for use in astronomy and geophysics.
SUMMARY OF THE INVENTION
The present invention overcomes the given drawbacks and provides an imaging immunoassay detection apparatus system and method capable of detecting and quantifying multiple light-emitting reactions from small volume samples simultaneously.
The present invention is very advantageous inasmuch as it is very rapid because it analyses all samples simultaneously, is extremely accurate because it requires no mechanical motion of components, has no repositioning errors as in sequential resolution, can use an internal standard such as a known sample to obtain comparative information, is adaptable with a filter to handle any particular wavelength of light, and is versatile in that it can detect assays requiring external light as well as those that do not require external light, thus being able to operate with immunoassays utilising luminescence and fluorescence and the like.
In brief, the present invention comprises an imaging system for detecting photons generated by chemical reactions comprising sample carrier means having a plurality of individual areas each containing individual chemical reactant samples capable of emitting photons if a reaction takes place, the plurality of reactant-containing areas being arranged in spaced relationship with respect to each other; imaging means associated with said carrier means for simultaneously receiving individual photons emitted from each area sample where a reaction is taking place; and means coupled to the photon-receiving imaging means for generating a signal representing the x-y location of each area sample generating a photon, whereby the reactants in each area sample having a reaction and the number of its photon emissions over any predetermined period of time may be simultaneously identified.
The invention also comprises a method of simultaneously detecting photons generated by a plurality of chemical reactions, comprising the steps of providing a plurality of individual chemical reactant samples each capable of emitting photons when a reaction takes place, the samples being arranged in spaced relationship with respect to each other, and simultaneously detecting the presence and x-y location of each photon emitted from any reacting samples, whereby the total number of photons emitted from each reacting sample over a predetermined period of time may be determined.
Thus, the present invention is not only extremely rapid and processes simultaneously multiple assays, but also enables considerable economies to be made in the use of often expensive reagents concerned because only small quantities of samples are required.
DESCRIPTION OF THE DRAWINGS
FIG. 1 is a diagrammatic representation of the novel photon detection system;
FIG. 2 is a diagrammatic representation of the imaging photon detector used in the system of FIG. 1;
FIG. 3 is a representation of both background noise signals and signals from discrete areas of reaction (whereby the background noise signals may be cancelled, leaving only reaction signals);
FIG. 4 represents a carrier in which multiple antibody labels may be used simultaneously or in which a standard reaction may be compared with other reactions;
FIG. 5 is a diagrammatic representation of how a wavelength interference filter may be used with the carrier of FIG. 4 to pass only a particular light wavelength, thereby allowing only photons of a particular wavelength corresponding to a labelled antibody to pass to the imaging detector;
FIG. 6 is a schematic representation of a circuit in a microprocessor for subtracting background noise from the sample signals to obtain an output signal representing substantially only pure photon emission from a reactant sample; and
FIG. 7 is a diagrammatic representation of the use of invisible ultraviolet radiation as a source of external light.
DETAILED DESCRIPTION
The apparatus of the present invention, which will be described in further detail below, may be utilised with any number of different assay techniques as stated earlier, but will be described with particular reference to the use of luminescent immunoassays in the detection of antigen-antibody reactions. More particularly, the invention can be employed to detect the characteristic reactions of labelled monoclonal and polyclonal antibodies with antigens found in samples such as urine, faeces, blood, milk and water and the like.
Polyclonal antibodies are well-known. Monoclonal antibodies may be prepared by the technique first described by Kohler and Milstein, Eur. J. Immunol. 6, 292 (1975). In order to detect the presence of particular antigens, the monoclonal antibodies may be labelled with a multitude of different labels, such as luminescent or fluorescent compounds. Further, the particular labels utilised in the present invention must be capable of emitting light once the antigen-antibody reaction occurs, and thus the reactions are designated as "light-emitting reactions". The present invention will be described in general with reference to a luminescent-labelled monoclonal antibody, although fluorescent labels may also be used as disclosed hereafter. As used herein, the term "reactants" means the combination of (1) a monoclonal antibody labelled with a luminescent or fluorescent compound, and (2) an antigen.
Luminescence is the emission of light by an atom or molecule as an electron is transferred to the ground state from a higher energy state. In both chemiluminescent and bioluminescent reactions, the free energy of a chemical reaction provides the energy required to produce an intermediate reaction or product in an electronically excited state. Subsequent decay back to the ground state is accompanied by emission of light. Bioluminescence is the name given to a special form of chemiluminescence found in biological systems such as the firefly, in which a catalytic protein or enzyme, such as luciferase, increases the efficiency of the luminescent reaction. When this luciferase enzyme is combined with its substrate, luciferin, in the presence of ATP (adenosine triphosphate), magnesium and oxygen, a flash of light is produced, whose intensity is proportional to the amount of ATP present in the sample. The firefly luciferase/luciferin/ATP system is as follows: ##STR1## where hν is the energy of a photon, h is the Planck constant, and ν is the frequency associated with the photon.
Assays of the invention can directly determine the number of live organisms in a sample, either because the presence of ATP in a test sample indicated live cells, or because of the presence of immunoglobulins labelled with a luminescence-detectable enzyme (like peroxidase or luciferase).
Chemiluminescent substances such as luminol may also be utilised in a horseradish peroxidase-catalysed oxidation, as follows: ##STR2##
In the present invention, the "light-emitting reactions" generate photons which are coupled to an imaging device such as an imaging photon detector, a charge-coupled device, or a vidicon tube (any of a variety of camera tubes having a photoconductive target). In the preferred embodiment, an imaging photon detector is used.
In particular, the reactions may be generated by reactants spatially arranged in individual areas on a sample carrier in a single row or column or by a two-dimensional array of reactants spatially arranged, for instance, in rows and columns. For example, a carrier may have an array, such as rows, of 1 mm outside diameter nylon tubes containing the labelled monoclonal antibodies, to which is added the specimen or specimens being tested for the presence of an antigen. The fluids involved are self-contained and of a very small volume. Thus, an advantage of the present invention is that the imaging photon detector can quantify (in 10 seconds or less) light emitted from multiple "light-emitting reactions", in volumes of 3 μl or less, i.e. much smaller than can be used in known apparatus.
Another carrier suitable for use with an imaging photon detector is a microtiter plate with multiple samples in rows and columns. A particular plate may contain as many as 96 individual wells. Each well contains different labelled monoclonal antibodies adsorbed on the surface of the plate. A portion of the specimen is added to each well. The presence and quantity of a particular antigen in an individual well is determined by the number of photons generated by the antigen-antibody reaction.
A third carrier involves the principle of using immobilised antibodies on a plurality of filaments; labelled monoclonal antibodies are immobilised in individual areas on a plurality of filaments. Each filament may bear a different labelled monoclonal antibody capable of emitting light upon the detection of an antigen. Because the reactions on the individual filaments generate light, the imaging photon detection system can quantitatively determine the presence of particular antigens.
The present invention envisages the use of any number of different types of multiple, chemically-produced, light-emitting reactions which can be imaged by the image photon detector. As the samples emit light, the present invention counts the individual photons impinging upon a light sensitive photocathode of an imaging photon detector.
Each of the above means for containing a plurality of reactants can be used in the apparatus system described below, in which the container is identified as the specimen carrier means.
The apparatus system will be described with reference to FIGS. 1 and 2.
FIG. 1 is a system for quantitative assay analysis of multiple biochemical images using an imaging photon detector. The system enables the detection of very low concentrations of substances present in fluid samples or specimens which, in the course of their reaction, emit light photons under certain conditions. In particular, the system has demonstrated sensitivity in the order of 10-16 and lower.
FIG. 1 shows a specimen carrier means 10 which may include a plurality of fluid samples all capable of simultaneously undergoing a reaction. Samples can be spaced in individual areas as a row or column or in a two-dimensional array of rows and columns as shown in FIG. 3 and FIG. 4, for example only. The reactions that produce light generate photons 12 which are focused by an optical system 14 to form the image of the light outputs of each of the samples on a photoconductive target forming a portion of an imaging photon detector (IPD) 16. The imaging photon detector 16 will be disclosed in detail hereinafter but is known in the art; it immediately converts incoming light into quantitative information which can be stored and processed within a memory of any conventional computing means such as a microprocessor 24.
The imaging detector 16 of the present invention takes simultaneous readings of discrete sample areas such as the small darker shaded orthogonal areas of FIG. 3 rather than averaging the readings of the entire sample area (including the carrier area surrounding the sample). Background noise, represented by the shading lines in FIG. 3, is caused by non-specific binding antigens or antibodies to the solid surface of the carrier, which are not washed away in the preparation of the carrier. Conventional detectors read these signals generated by this undesirable binding and, because these conventional detectors average the signal over the entire sample area, they interpret these undesired false signals as a positive reaction. Background noise effectively decreases the sensitivity of the assay at relatively low levels of concentration, where the positive reaction signal has nearly the same intensity level as the background noise.
The present invention eliminates the background noise problem by simultaneously reading the signal from the background environment and the signal from the concentrated reaction area and comparing the two readings. Because the present imaging immunoassay detection system can read signals from numerous discrete reaction areas at the same instant, a real time measurement of the signals from the discrete areas of reaction in a two-dimensional array can be taken, averaged, and compared with the signal representing the background noise caused by the non-specific binding. The computer 24 can analyse and display the results by subtracting from the signals representing the discrete areas of reactions the signals representing the background noise, as shown in FIG. 6, thereby leaving the pure reaction signals.
Further, since the present system can simultaneously evaluate a carrier, such as a 96-well microtiter tray, without repositioning the carrier or tray as in systems using sequential detection, resolution errors that occur from imprecise mechanical repositioning of the samples between measurements as required in the prior art are eliminated.
Since the present imaging immunoassay detection system can look at more than one discrete reaction at a time, contrasting reactions can be analysed relative to one another. By way of illustration, in a two-dimensional array of samples as in a microtiter tray represented in FIG. 4, reactions can be compared side-by-side simultaneously. The amount of photons generated by each reaction can be read and analysed by computer 24 and the relative extent of reaction compared. In this way, a more accurate comparison can be made between specific samples, thus providing better test results. As an example, a negative reaction may be placed in a discrete area A in FIG. 4, to serve as a control for purposes of comparison with a positive reaction in a discrete area B. The negative reaction in discrete area A may still generate spurious signals caused by non-specific binding, as pointed out earlier. This background noise level is potentially constant across a given carrier such as a microtiter tray and is useful in setting up a base level of signal generation from which more positive reaction can be compared.
Thus, the present imaging system is capable of rapid quantitative analysis of samples. Because of its unique ability to simultaneously read and analyse numerous samples, the time necessary to produce results is dramatically reduced.
Furthermore, the sensitivity of the present imaging system allows for very accurate measurements even at very low concentrations of the samples. For instance, an imaging photon detector is capable of measuring individual photons of light. By using amplifiers, the system is able to register very low concentrations of materials and is therefore useful in areas such as diagnosing for the presence of infectious organisms, as well as drug monitoring and disease detection.
Because of its sensitivity, the imaging system can not only detect minute quantities of a reaction samples, but can also read a very small area of reaction. Thus, the amount of reagent and the area which are needed to conduct the assay are less then before, thereby minimising the cost of reagents and carrier materials.
The output of the imaging photon detector 16 on line 18 comprises analog signals which represents the x-y spatial correspondence of each detected photon, thus identifying electrically the x-y address of the sample or specimen that produced the light. These analog signals are coupled to an analog-to-digital (A/D) converter 20 which produces digital output signals on lines 22 representing the spatial orientation of the specimen source producing the photon received by the imaging photon detector 16 and thus identifying the particular sample or specimen which produces the photon. The digital signals 22 are coupled to a microprocessor 24 which stores and analyses the image information and can be programmed to display it in any desired format. The reactions continue to generate light throughout any desired predetermined period of time, e.g. as little as 10 seconds or less, and the number of photons produced by each reacting sample is accumulated in the memory of microprocessor 24. Thus, microprocessor 24 produces signals on line 26 to video display 28 and printer 30 for visual display and analysis of the light received, and accumulated, from samples 10.
A bar chart may be displayed on video terminal 28 which identifies each of the samples and illustrates the relative amount of light or number of photons being generated by each sample. Such a bar chart could also be produced, for a permanent record, by printer 30.
Also, a two-dimensional image of the array of samples as they are physically located (i.e. their x-y address) can be produced, the intensity of the light generated by each sample being indicated either in colour or by numerals, thus identifying which sample is generating the greatest amount of light. Obviously, the microprocessor 24 can perform any operation on the samples as desired to correct and calibrate the image and to compensate for any inherent noise in the system such as by subtracting the background noise, as explained earlier. Noise also may be reduced by cooling the imaging photon detector 16 with a cooling unit 15 in any well known manner such as by circulating a cooling liquid or a refrigerant about the imaging photon detector 16. Cooling the detector 16 reduces the tendency for free electrons to be emitted from elements of the detector 16, and which assist in generating the background noise.
FIG. 2 is a diagrammatic representation of the construction details of the imaging photon detector used in the preferred embodiment herein and which is known in the art. The detector may be type IPDG1 or type PIDF1 manufactured by Instrument Technology Limited in East Sussex, England. The imaging photon detector 16 is a two-dimensional imaging sensor capable of detecting extremely weak radiation, e.g, capable of detecting an ATP content in the sample down to as low as 10-16 moles/sample. As indicated earlier, that image is produced in analog form which is converted through an analog-to-digital converter 20 to a digital form for use by the microprocessor 24.
Light is composed of individual photons. Each individual photon has an extremely small amount of energy associated therewith. In most common images, the light contains fluxes of millions or billions of photons per square centimeter and per second. Using the imaging photon detector 16, each incoming photon has a high probability of detection by the photocathode 32.
The photoconductive target 32 can thus be thought of as equivalent to a photographic film except that it has a sensitivity of the order of 100 times greater. When a photon strikes the light sensitive photocathode 32, a photoelectron is released from photocathode 32 and is immediately accelerated into a series of microchannel plate intensifiers or amplifiers 34. As a result of the intensification created by microchannel plates 34, a gain in the range of 3×106 to 3×107 electrons is emitted from the rear of each microchannel plate for each incident photoelectron and thus corresponds to each initially detected photon. The combination of the microchannel plates 34 thus enables extremely small amounts of light to be detected.
A resistive anode encoder 36 located immediately behind the microchannel plates 34 translates the electron burst into signals which can be processed easily into a two-dimensional x-y address of the detected photon and thus the sample. Thus, the analog readout of the resistive anode 36 on line 18 in FIG. 1 is used to present a linear x-y registration of each photoelectron event. The read-out through four orthogonal electrodes 38 is suitably processed to provide digital representation of the x-y position of the incident photoelectron (and thus the sample) by analog-to-digital converter 20 and microprocessor 24, both shown in FIG. 1. Thus, by the use of the imaging photodetector 16, the full image of all of the samples 10 in two dimensions is created by integrating the image focused onto the photocathode 32, photon-by-photon. Thus, the present system detects and presents information relating to multiple imaging, presents the information immediately upon the occurrence of the emitted light, detects extremely small amounts of light down to and including a single photon, and quantifies such information for each specific x-y sample or specimen address.
Instead of an imaging photon detector (which is preferred), the system may use a charge-coupled device (CCD) as the imaging device 16. CCD's are well known in the art. They are used in conjunction with an optical lensing system (such as optical system 14 in FIG. 1) which focuses light from the object being investigated (sample array 10 in FIG. 1) on to the CCD. Varying amounts of light from individual samples are incident on individual pixels within the CCD and charge the pixels to different levels proportional to the incident light. Thus the optical information or light from sample array 10 is available in analog form across the pixels of CCD array 16. The analog information is then shifted out of the CCD and converted to digital form in a well known manner by the analog-to-digital converter 20 and is then coupled to a memory in computer 24 where the various measurement levels and comparisons can be made by appropriate manipulation of the digital information. See "Imaging", The Optical Industry and System Purchasing Directory, 1983, pp. E-72 to E-74.
As is well known in the prior art, the individual pixels within a CCD array are closely spaced and arranged horizontally in rows and vertically in columns so that a given CCD imaging device 16 provides a fixed number of pixels of information. For instance, some CCD's have 320 vertical columns of pixels and 512 horizontal rows of pixels.
CCD's have several characteristics which make them advantageous in the present invention as an imaging device. CCD's are small and rugged and have closely spaced pixels and are therefore useful where, as here, precise measurements are required. They also receive an image by the direct reception of light energy without being scanned, and store the received data until the data are transferred to another storage device. Further, the data received from the CCD can be processed by simple comparison or detection techniques, thereby avoiding complex and major time-consuming sampling techniques ordinarily used to process such data.
Another imaging device which can be used instead of an imaging photon detector or a CCD is a vidicon tube. The name vidicon is generally applied to any of a variety of tubes having a photoconductive target. The vidicon operates in a well known manner and utilises an electron beam to scan a light-sensitive photoconductive target. A transparent conductive layer applied to the front side of the photoconductor serves as a signal or target electrode. The target electrode is operated at a positive voltage with respect to the back side of the photoconductor which operates at cathode (near zero) voltage. In operation, the scanning beam initially charges the back side of the target electrode to cathode potential. When a light pattern (light photon) is focused on the photoconductor, its conductivity increases in the illuminated areas and the back side of the target charges to more positive values. The electron beam then reads the signal by depositing electrons on the positively charged areas, thereby providing a capacitively coupled signal at the signal output electrode. See "Imaging Devices", RCA Solid State Devices, 19, pp. 3-9.
Thus, as used in FIG. 1, a vidicon 16 receives the photons or light output from the respective reactions through optics 14 and produces the analog output on line 18 as described earlier. The analog output on line 18 is coupled to the analog-to-digital converter 20 from which digital signals are processed in the same manner as for the imaging photon detector.
It is also possible to use multiple antibody labels with the imaging immunoassay detection system of the present invention. Different antibodies are labelled with different indicators and correspond to different discrete areas on the carrier medium. Thus, with regard to FIG. 4, discrete area A may have an antibody labelled with an indicator such as luciferase, discrete area B may have an antibody labelled with an indicator such as a bacterial reductase, and so forth. Since each indicator generates a different wavelength of light, each discrete area of each antibody has its own particular wavelength of light which can be detected by imaging device 16. As can be seen in FIG. 5, a wavelength interference filter 40 of the desired characteristics is placed between samples 10 and optics 14 such that only photons of a particular wavelength corresponding to an antibody labelled with a particular indicator pass through to the imaging detector 16. In this manner, the novel imaging immunoassay detection system can be made wavelength selective, thereby permitting greater flexibility and sensitivity.
It will be understood, of course, that if a fluorescing material, such as fluorescein, is used as the label, invisible ultraviolet light or black light will have to be used. FIG. 7 illustrates such apparatus, wherein an ultraviolet light source 54 is powered by an appropriate power source 56. Ultraviolet light rays 58 impinge on samples in carrier 10 which fluoresce if a reaction takes place. The remainder of the circuit operates as described above in connection with FIG. 1.
As shown in FIG. 6, the signals detected by imaging device 16, representing background noise and sample signals combined, are stored in a memory 42 of microprocessor 24. The detected signals representing background noise alone are stored in a memory 44 of microprocessor 16. By coupling these two stored signals on lines 46 and 48 to an arithmetic unit 50, and subtracting one from the other an output signal is obtained on a line 52, which represents substantially only pure photon emission from any selected reactant sample. Thus, background noise is substantially eliminated or minimised.
The system of the present invention can be used in conjunction with labelled DNA or RNA probes instead of antibodies as a diagnostic tool. DNA probes or RNA probes are specific sequences of nucleotides that are complementary to particular sequences of a sample piece of DNA or RNA. These probe pieces of DNA or RNA can be labelled with an indicator so as to generate a signal, analogous to an immunoassay, and would be contained in a carrier 10 such as shown in FIG. 1. In use, the DNA or RNA is first removed from a cell or other structure in a sample containing a DNA or RNA sequence. The DNA or RNA is bound to a surface such as nitrocellulose, and is then denatured so that its complementary strands are separated. The DNA or RNA probe, labelled with an indicator, is then added to the sample and, if the specific complementary sequence of the probe is present in the sample, the sample and probe will combine. The unbound label is washed away and the sample containing bound labelled probe is read in the manner described hereinabove with reference to FIG. 1.
Isotope-labelled assays are also within the scope of the present invention. In such an assay, the indicator component is labelled with an isotope, such as phosphorus-32 or iodine-125, which emits gamma radiation. In the performance of a radioisotopic assay, the isotope-labelled component, typically an antibody, is bound to the analyte of interest, the unbound label is washed away from the reaction zone, and the zone is read. The reading of the central reaction zone is accomplished in this embodiment by the incorporation of a phosphor screen. Phosphor screens are well known in the art and are used to convert electron energy into radiant energy. These screens are composed of a thin layer of luminescent crystals, phosphors, which emit light when bombarded by electrons. In the present case, the phosphor screen receives gamma radiation from the labelled analyte and, in turn, emits photons which are received by the detection system. Thus, in FIG. 1, carrier 10 would be the phosphor screen which received electrons from any reaction and emits light 12 which is focused by optics 14 and processed in the manner explained previously. In this manner, gamma particles are converted into detectable photons which are received and processed as described hereinabove. Other types of gamma-to-photon conversion means are also usable and within the scope of the present invention.
As an illustration of the sensitivity of the IPD array detector system, the well established firefly luciferase/luciferin-based assay for ATP provides a useful reference. Thus, using the standard "Lumac" firefly luciferase/luciferin reagents for the bioluminescent ATP assay in the Lumac Biocounter luminometer, the lower limit for the assay (carried out as recommended by the manufacturer) is set by the "background" count of photons (of about 10/second) typically experienced. This sets the lower limit of the determination at about 5×10-15 moles ATP per sample. In contrast, using the IPD system described above, the lower limit of the determination, using similar criteria, is set at about 5×10-17 moles ATP.
The invention will be further illustrated in conjunction with the following Example, which is set forth for purposes of illustration only and not by way of limitation.
EXAMPLE
Monoclonal antibodies are prepared according to the method of Kohler and Milstein noted above. In particular, an antibody to Shigella is prepared by the procedure described in WO-A-86/00296 and labelled with luminescent compounds such as the firefly luciferase/luciferin/ATP system. These luminescent labelled antibodies are then adsorbed onto the surface of a microtiter tray. Additionally, each well of the tray may contain labelled monoclonal antibodies to different antigens, thus allowing diagnosis for the presence of a wide variety of different antigens at the same time. This microtiter tray thus contains a number of known antibodies at known x-y addresses or areas on the tray. The tray is then washed with the specimen containing the unknown antigen(s) and an antigen-antibody reaction occurs. Next, the tray is rinsed and unbound antibodies are removed. Then, the tray is placed in the specimen carrier holder of the imaging photon detecting system described above. The presence and amount of the unknown antigen(s) in the specimen are determined by the photons generated by the characteristic antigen-antibody reactions and their x-y location on the microtiter tray.
While the invention has been described in connection with a preferred embodiment, it is not intended to limit the scope of the invention to the particular form set forth, but, on the contrary, it is intended to cover such alternatives, modifications and equivalents as may be included within the spirit and scope of the invention as defined by the appended claims.

Claims (48)

What is claimed is:
1. A system for detecting photons generated by chemical reactions comprising:
a. sample carrier means having a plurality of individual discrete separated areas each containing a separate and independent chemical reactant sample which will emit a number of light photons when a reaction takes place, said plurality of reactant-containing discrete separated areas being arranged in two-dimensional spaced relationship with respect to each other and having spaces therebetween;
b. photon-receiving means associated with said sample carrier means for simultaneously receiving individual photons emitted from each discrete area sample and from said spaces when photons are emitted from said spaced; and
c. signal generating means coupled to said photon-receiving means for generating signals representing a location of each of said discrete area sample and each of said spaces generating a photon, whereby the sample location of each area having a reaction, the location of each of said spaces generating a photon and said number of their photon emissions over any predetermined period of time will be simultaneously identified.
2. A system as in claim 1 wherein:
a. said photon-receiving means is constructed so as to respond to photons emitted from said spaces for generating signals representing background noise which consists of emitted light photons from said spaces between said chemical reactant samples; and
b. wherein there is included means for subtracting said background noise signals from said signals representing photon emission from each of said samples to produce a resulting signal whereby said resulting signal represents substantially only pure emissions from said reactant samples.
3. A system as in claim 1 further including:
a. computing means coupled to said signal generating means for receiving and storing each of said signals whereby said location of each of said spaces generating a photon and the number of photons generated by each of said spaces and each sample having a reaction over said any predetermined period of time can be accessed; and
b. display means coupled to said computing means for presenting a representation of each of said samples and the number of its photon emissions.
4. A system as in claim 2 further including:
a. computing means coupled to said signal generating means for receiving and storing each of said signals whereby said location of each of said spaces generating a photon and the number of photons generated by each of said spaces and each sample having a reaction over said any predetermined period of time can be accessed; and
b. display means coupled to said computing means for presenting a representation of each of said samples and the number of its photon emissions.
5. A system as in claim 3 wherein said display means is a video display.
6. A system as in claim 4 wherein said display means is a printer.
7. A system as in claim 3 wherein said computing means is a microprocessor.
8. A system as in claim 1 wherein said signal generating means is a photomultiplier tube having a photoconductive target for producing reaction location output signals representing the number of photons emitted by each reaction, and the space output signals representing the number of photons emitted by said spaces.
9. A system as in claim 1 wherein said signal generating means is a charge coupled device for producing reaction location output signals representing the number of photons emitted by each reaction, and the number of photons emitted by said spaces.
10. A system as in claim 1 wherein said signal generating means is a vidicon tube for producing reaction location output signals representing the number of photons emitted by each reaction and the number of photons emitted by said spaces.
11. A system as in claim 4 wherein each of said chemical reactant samples comprises:
a. an antibody;
b. an antigen; and
c. an indicator which labels said antibody and which generates said photons of light when a reaction occurs between said antibody and said antigen.
12. A system as in claim 3 wherein at least one of said chemical reactant samples contains an indicator which emits light of different wavelength than others of said chemical reactant samples.
13. A system as in claim 12 further comprising:
a. a photoconductive target forming a portion of said signal generating means; and
b. an optics system constructed so as to focus light photons from said reactant samples on said photoconductive target to generate said sample location output signals representing the number of said photon emissions from each said sample.
14. A system as in claim 13 further comprising a specific wavelength light interference filter positioned between said sample carrier means and said optics system for passing only a specific light wavelength corresponding to said at least one chemical reactant indicator being said indicator which emits light of different wavelength than said others of said chemical reactant samples whereby only said at least on chemical reactant is monitored by said system for photon emission.
15. A system as in claim 2 wherein said photon emitting reactant samples are arranged in discrete areas forming a single row or column.
16. A system as in claim 2 wherein said photon emitting reactant samples are arranged in discrete areas forming a two-dimensional array of rows and columns.
17. A system as in claim 15 or 16 further including:
a. a first reactant sample in one of said discrete areas;
b. a second different reactant sample in a second one of said discrete areas; and
c. means for comparing signals representing light photons emitted from said second reactant sample with signals representing light photons emitted from said first reactant sample, whereby one reactant sample may be compared with another.
18. A system as in claim 17 wherein said second reactant sample is a test sample and said first reactant sample is a control sample representing a desired standard control reaction, whereby said test sample may be compared with said control sample.
19. A system as in claim 2 wherein:
a. said signals generated by said signal generating means include photon representation analog signals severally representing the numbers of photons generated by each photon-generating sample over a predetermined period of time, and further including
b. an analog-to-digital converter coupled to said signal generating means for converting said analog signals representing said numbers of photons to digital signals;
c. a microprocessor coupled to said analog-to-digital converter; and
d. storage means in said microprocessor having a plurality of locations therein corresponding to said plurality of reactant samples for storing said digital signals.
20. A system as in claim 2 wherein each of said chemical reactant samples comprises:
a. a sample containing a sequence of nucleic acids;
b. a nucleic acid probe specific for its complementary sequence in nucleic acids respectively; and
c. an indicator which labels said nucleic acid probe and which generates said photons of light when a reaction occurs between said probe and its said complementary sequence.
21. A system as in claim 2 wherein each of said chemical reactant samples comprises:
a. an isotope-labeled antibody;
b. an analyte of interest whereby when a reaction occurs between said labeled antibody and said analyte of interest, gamma rays are generated; and
c. a phosphor screen for receiving said gamma rays and generating said photons of light.
22. A system as in claim 1 wherein:
a. said photon receiving-means is constructed so as to respond to photons emitted from said spaces for generating signals representing background noise which consists of emitted light photons from said spaces between said reactant samples; and
b. wherein there is included means for substracting said background noise signals from said signals representing photon emission from each of said samples whereby the resulting signal represents substantially only pure emissions from said reactant samples.
23. A system as in claim 22 further including:
a. computing means coupled to said signal generating means for receiving and storing each of said signals whereby the location and number of photons generated by each of said spaces and each sample having a reaction over said any predetermined period of time can be accessed; and
b. display means coupled to said computing means for presenting a representation of each of said samples and the number of its photon emissions.
24. A system as in claim 23 wherein said display means is a video display.
25. A system as in claim 23 wherein said display means is a printer.
26. A method of detecting photons generated by a chemical reaction comprising:
a. proving a plurality of discrete separated individual and independent chemical reactant samples each capable of reacting with a specific substance and emitting light photons when a reaction takes place, said reactant samples being arranged in two-dimensional spaced apart relationship with each other;
b. creating spaces of predetermined size between said reactant samples, said spaces emitting spurious photons representing background noise;
c. adding to each of said samples a specimen potentially containing at least one unknown specific substance such that a reaction generating photons occurs when said specific substance is present in said specimen;
d. simultaneously generating first signals detecting presence of each photon emitted within each of said spaces and from any of said samples and a location of each of said reactant samples from which a photon is emitted, whereby a total number of photons emitted from said spaces and from each individual reactant sample over a predetermined period of time will be determined, and generating a background signal representing background noise.
27. A method of detecting photons generated by a chemical reaction as in claim 26 further including accumulating the number of photons emitted by any reactant samples over a predetermined period of time whereby the total photon emission of any reactant sample may be determined.
28. A method of detecting photons generated by a chemical reaction as in claim 26 further including subtracting said signal representing background noise from said first signals thereby to create other signals representing pure emissions from said reactant samples.
29. A method of detecting photons generated by a chemical reaction as in claim 26 further including storing in a microprocessor numbers severally corresponding to the numbers of photons emitted by said reactant samples over a predetermined period of time, thereby enabling the photon emissions of any reactant sample to be compared with the number of photon emissions from other reactant samples.
30. A method of detecting photons generated by a chemical reaction as in claim 29 further including displaying for each reactant sample a representation of the total accumulation of the number of photons emitted by that sample over a predetermined period of time thereby giving a visual indication of the number of photons emitted by said each reactant sample over said predetermined period of time.
31. A method for detecting a reaction comprising:
a. locating a plurality of labeled compounds onto discreet and separated areas of a carrier;
b. adding to at least one of said labeled compounds a specimen potentially containing at least one unknown substance of a type which produces a reaction with said at least one of said labeled compounds when said unknown substance is present and comprises a particular substance, any said reaction generating light photons;
c. individually detecting any of said reaction that may occur by simultaneously detecting location of any said reaction and number of light photons emitted by each said reaction;
d. detecting any spurious photons emitted in spaces between said discreet and separated areas of said carrier and generating from said spurious photons a background noise signal representing background noise for said carrier; and
e. adjusting said number of photons thereby to essentially eliminate any noise component therefrom.
32. A method as in one of claims 26 31 wherein said at least one unknown substance is an antigen and further comprising contacting at least a portion of said specimen with a labeled monoclonal antibody.
33. A method as in claim 26 further including utilizing an imaging detector to detect presence and location of each photon emitted by any of said reacting samples.
34. A method as in claim 33 further including utilizing an imaging photon detector as said imaging detector.
35. A method as in claim 33 further including utilizing a charge coupled device as said imaging detector.
36. A method as in claim 33 further including utilizing a vidicon tube as said imaging detector.
37. A method as in claim 26 further comprising forming each of said reactant samples with an antibody, an antigen, and an indicator which labels said antibody and which generates said light photons when a reaction occurs between said antibody and said antigen.
38. A method as in claim 37 further including forming at least one of said chemical reactants with an indicator which emits light of different wavelength than others of said chemical reactants indicators.
39. A method as in claim 38 further including:
a. forming a portion of said photon detecting means as a photoconductive target; and
b. focusing said light photons from said reactant samples on said photoconductive target with an optics system to generate signals representing presence and location of said photon emissions from said samples.
40. A method as in claim 39 further including positioning a specific wavelength light interference filter between said reactant samples and said optics system for passing only a specific light wavelength corresponding to said at least one of said chemical reactants indicators being said indicator which emits light of different wavelength than the others of said chemical reactants indicators whereby only said at least one chemical reactants is monitored by said system for photon emission.
41. A method as in claim 26 further including:
a. detecting background noise signals consisting of said spurious light photons emitted from said spaces between said reactant samples; and
b. subtracting said background noise signals from said signals representing photon emissions from each of said samples whereby a resulting signal represents substantially only pure photon emissions from said reactant samples.
42. A method as in claim 26 further comprising arranging said photon emitting reactant samples in discrete areas forming a single linear sequence of either a row or column.
43. A method as in claim 26 further comprising arranging said photon emitting reactant samples in discrete areas forming a two-dimensional array of rows and columns.
44. A method as in claim 42 or 43 further comprising:
a. placing a first reactant sample in one of said discrete areas;
b. placing a second different reactant sample in a second one of said discrete areas; and
c. comparing signals representing the number of light photons emitted from said sample in said second one of said areas with said signals representing light photons emitted from said first sample whereby one sample may be compared with another.
45. A method as in claim 44 further comprising:
a. forming said first sample of reactants providing a desired standard control reaction; and
b. forming said second reactant sample as a test sample whereby said test sample may be compared with said control sample.
46. A method as in claim 26 wherein the step of generating first signals detecting the presence of each photon emitted and the location of each of said reactant samples from which a photon is emitted is the step of generating analog signals.
47. A method as in claim 46 further including:
a. converting said analog signals to digital signals;
b. coupling said digital signals to a microprocessor; and
c. storing said digital signals in a plurality of memory locations in said microprocessor.
48. A method of detecting photons generated by a chemical reaction as in claim 26 further including the step of subtracting said background signal representing background noise from said first signals thereby to create other signals representing pure emissions from said reactant samples.
US07/449,502 1985-03-06 1989-12-01 Imaging immunoassay detection system with background compensation and its use Expired - Lifetime US5096807A (en)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
GB858505822A GB8505822D0 (en) 1985-03-06 1985-03-06 Array systems
GB8505822 1985-03-06
GB8512041 1985-05-13
GB858512041A GB8512041D0 (en) 1985-05-13 1985-05-13 Immunoassay
GB858517042A GB8517042D0 (en) 1985-07-05 1985-07-05 Imaging immunoassay detection system
GB8517042 1985-07-05
US83599286A 1986-03-04 1986-03-04

Publications (1)

Publication Number Publication Date
US5096807A true US5096807A (en) 1992-03-17

Family

ID=27449642

Family Applications (1)

Application Number Title Priority Date Filing Date
US07/449,502 Expired - Lifetime US5096807A (en) 1985-03-06 1989-12-01 Imaging immunoassay detection system with background compensation and its use

Country Status (1)

Country Link
US (1) US5096807A (en)

Cited By (169)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5340747A (en) * 1992-03-09 1994-08-23 Difco Laboratories, Inc. Diagnostic microbiological testing apparatus and method
US5374892A (en) * 1993-03-04 1994-12-20 Georgia Tech Research Corporation Digital electrochemical instrument with background compensation
US5413939A (en) * 1993-06-29 1995-05-09 First Medical, Inc. Solid-phase binding assay system for interferometrically measuring analytes bound to an active receptor
WO1995012808A1 (en) * 1993-11-01 1995-05-11 Nanogen, Inc. Self-addressable self-assembling microelectronic systems and devices for molecular biological analysis and diagnostics
US5432099A (en) * 1987-08-06 1995-07-11 Multilyte Limited Determination of ambient concentation of several analytes
US5447687A (en) * 1993-03-19 1995-09-05 Lewis; Scott C. Luminometer
WO1996001836A1 (en) * 1994-07-07 1996-01-25 Nanogen, Inc. Self-addressable self-assembling microelectronic systems and devices for molecular biological analysis and diagnostics
WO1996007917A1 (en) * 1994-09-09 1996-03-14 Nanogen, Inc. Automated molecular biological diagnostic system
US5595708A (en) * 1993-08-27 1997-01-21 Becton Dickinson And Company System for detecting bacterial growth in a plurality of culture vials
US5653939A (en) * 1991-11-19 1997-08-05 Massachusetts Institute Of Technology Optical and electrical methods and apparatus for molecule detection
US5670113A (en) * 1991-12-20 1997-09-23 Sibia Neurosciences, Inc. Automated analysis equipment and assay method for detecting cell surface protein and/or cytoplasmic receptor function using same
US5677196A (en) * 1993-05-18 1997-10-14 University Of Utah Research Foundation Apparatus and methods for multi-analyte homogeneous fluoro-immunoassays
US5686046A (en) * 1995-07-13 1997-11-11 Chiron Diagnostics Corporation Luminometer
WO1997045730A1 (en) * 1996-05-30 1997-12-04 Biodx Miniaturized cell array methods and apparatus for cell-based screening
WO1998026277A2 (en) * 1996-12-12 1998-06-18 Prolume, Ltd. Apparatus and method for detecting and identifying infectious agents
US5827748A (en) * 1997-01-24 1998-10-27 The United States Of America As Represented By The Secretary Of The Navy Chemical sensor using two-dimensional lens array
US5837551A (en) * 1993-12-24 1998-11-17 Ekins; Roger P. Binding assay
US5849486A (en) * 1993-11-01 1998-12-15 Nanogen, Inc. Methods for hybridization analysis utilizing electrically controlled hybridization
WO1999019510A1 (en) * 1997-10-10 1999-04-22 President And Fellows Of Harvard College Surface-bound, double-stranded dna protein arrays
US5919712A (en) * 1993-05-18 1999-07-06 University Of Utah Research Foundation Apparatus and methods for multi-analyte homogeneous fluoro-immunoassays
US5942443A (en) * 1996-06-28 1999-08-24 Caliper Technologies Corporation High throughput screening assay systems in microscale fluidic devices
US5981202A (en) * 1994-11-15 1999-11-09 Biosensor Laboratories Co., Ltd. Two-dimensional solid phase assay
US6025985A (en) * 1997-07-16 2000-02-15 Ljl Biosystems, Inc. Moveable control unit for high-throughput analyzer
US6048690A (en) * 1991-11-07 2000-04-11 Nanogen, Inc. Methods for electronic fluorescent perturbation for analysis and electronic perturbation catalysis for synthesis
US6051380A (en) * 1993-11-01 2000-04-18 Nanogen, Inc. Methods and procedures for molecular biological analysis and diagnostics
US6068818A (en) * 1993-11-01 2000-05-30 Nanogen, Inc. Multicomponent devices for molecular biological analysis and diagnostics
US6084669A (en) * 1998-05-01 2000-07-04 Roche Diagnostics Corporation Fluorescent light measuring device and an apparatus wherein such a device is used
US6097025A (en) * 1997-10-31 2000-08-01 Ljl Biosystems, Inc. Light detection device having an optical-path switching mechanism
US6103479A (en) * 1996-05-30 2000-08-15 Cellomics, Inc. Miniaturized cell array methods and apparatus for cell-based screening
US6113886A (en) 1996-02-06 2000-09-05 Bruce Bryan Bioluminescent novelty items
US6132685A (en) * 1998-08-10 2000-10-17 Caliper Technologies Corporation High throughput microfluidic systems and methods
US6225059B1 (en) 1993-11-01 2001-05-01 Nanogen, Inc. Advanced active electronic devices including collection electrodes for molecular biological analysis and diagnostics
US20010000723A1 (en) * 1998-06-16 2001-05-03 Mcluen Gary R. Multi-well rotary synthesizer
US6232107B1 (en) 1998-03-27 2001-05-15 Bruce J. Bryan Luciferases, fluorescent proteins, nucleic acids encoding the luciferases and fluorescent proteins and the use thereof in diagnostics, high throughput screening and novelty items
US6254827B1 (en) 1993-11-01 2001-07-03 Nanogen, Inc. Methods for fabricating multi-component devices for molecular biological analysis and diagnostics
US6268218B1 (en) 1996-05-09 2001-07-31 3-Dimensional Pharmaceuticals, Inc. Method for sensing and processing fluorescence data from multiple samples
US6267858B1 (en) * 1996-06-28 2001-07-31 Caliper Technologies Corp. High throughput screening assay systems in microscale fluidic devices
US6271042B1 (en) * 1998-08-26 2001-08-07 Alpha Innotech Corporation Biochip detection system
US6287517B1 (en) 1993-11-01 2001-09-11 Nanogen, Inc. Laminated assembly for active bioelectronic devices
US6297018B1 (en) 1998-04-17 2001-10-02 Ljl Biosystems, Inc. Methods and apparatus for detecting nucleic acid polymorphisms
US6309602B1 (en) 1993-11-01 2001-10-30 Nanogen, Inc. Stacked, reconfigurable system for electrophoretic transport of charged materials
US6309601B1 (en) 1993-11-01 2001-10-30 Nanogen, Inc. Scanning optical detection system
US6317207B2 (en) 1999-02-23 2001-11-13 Ljl Biosystems, Inc. Frequency-domain light detection device
US6315953B1 (en) 1993-11-01 2001-11-13 Nanogen, Inc. Devices for molecular biological analysis and diagnostics including waveguides
US6319472B1 (en) 1993-11-01 2001-11-20 Nanogen, Inc. System including functionally separated regions in electrophoretic system
US6326605B1 (en) 1998-02-20 2001-12-04 Ljl Biosystems, Inc. Broad range light detection system
US6329209B1 (en) * 1998-07-14 2001-12-11 Zyomyx, Incorporated Arrays of protein-capture agents and methods of use thereof
US6331274B1 (en) 1993-11-01 2001-12-18 Nanogen, Inc. Advanced active circuits and devices for molecular biological analysis and diagnostics
US6355432B1 (en) 1989-06-07 2002-03-12 Affymetrix Lnc. Products for detecting nucleic acids
US6375899B1 (en) 1993-11-01 2002-04-23 Nanogen, Inc. Electrophoretic buss for transport of charged materials in a multi-chamber system
US6379895B1 (en) 1989-06-07 2002-04-30 Affymetrix, Inc. Photolithographic and other means for manufacturing arrays
US6403367B1 (en) 1994-07-07 2002-06-11 Nanogen, Inc. Integrated portable biological detection system
US6403957B1 (en) 1989-06-07 2002-06-11 Affymetrix, Inc. Nucleic acid reading and analysis system
US20020094116A1 (en) * 2000-08-25 2002-07-18 Amnis Corporation Method and apparatus for reading reporter labeled beads
US20020110932A1 (en) * 1998-07-14 2002-08-15 Peter Wagner Microdevices for screening biomolecules
US20020119579A1 (en) * 1998-07-14 2002-08-29 Peter Wagner Arrays devices and methods of use thereof
US20020119484A1 (en) * 1994-07-07 2002-08-29 Nanogen, Inc. Primer extension detection methods on active electronic microarrays
US20020132272A1 (en) * 1998-07-14 2002-09-19 Peter Wagner Non-specific binding resistant protein arrays and methods for making the same
US20020137096A1 (en) * 1989-06-07 2002-09-26 Affymetrix, Inc. Apparatus comprising polymers
US20020146734A1 (en) * 2001-02-21 2002-10-10 Amnis Corporation Method and apparatus for labeling and analyzing cellular components
US6466316B2 (en) 1998-07-27 2002-10-15 Ljl Biosystems, Inc. Apparatus and methods for spectroscopic measurements
US6469311B1 (en) 1997-07-16 2002-10-22 Molecular Devices Corporation Detection device for light transmitted from a sensed volume
US20020155492A1 (en) * 1990-12-06 2002-10-24 Affymetrix, Inc. Arrays for detecting nucleic acids
US6483582B2 (en) 1998-07-27 2002-11-19 Ljl Biosystems, Inc. Apparatus and methods for time-resolved spectroscopic measurements
WO2002103335A1 (en) * 2001-06-18 2002-12-27 Amnis Corporation Spectral deconvolution of fluorescent markers
US20030039997A1 (en) * 1997-09-22 2003-02-27 Aventis Research And Technologies Gmbh & Co. Kg Pentopyranosyl nucleic acid arrays, and uses thereof
US20030059929A1 (en) * 1993-11-01 2003-03-27 Nanogen, Inc. Methods for electronic synthesis of complex structures
US20030073122A1 (en) * 1993-11-01 2003-04-17 Nanogen, Inc. Methods for determination of single nucleic acid polymorphisms using a bioelectronic microchip
US6551784B2 (en) 1989-06-07 2003-04-22 Affymetrix Inc Method of comparing nucleic acid sequences
US20030086608A1 (en) * 2001-07-17 2003-05-08 Amnis Corporation Computational methods for the segmentation of images of objects from background in a flow imaging instrument
US20030092098A1 (en) * 2000-03-15 2003-05-15 Bruce Bryan Renilla reniformis fluorescent proteins, nucleic acids encoding the fluorescent proteins and the use thereof in diagnostics, high throughput screening and novelty items
US6566495B1 (en) 1989-06-07 2003-05-20 Affymetrix, Inc. Very large scale immobilized polymer synthesis
US6569631B1 (en) 1998-11-12 2003-05-27 3-Dimensional Pharmaceuticals, Inc. Microplate thermal shift assay for ligand development using 5-(4″dimethylaminophenyl)-2-(4′-phenyl)oxazole derivative fluorescent dyes
US6569382B1 (en) 1991-11-07 2003-05-27 Nanogen, Inc. Methods apparatus for the electronic, homogeneous assembly and fabrication of devices
US6573039B1 (en) 1997-02-27 2003-06-03 Cellomics, Inc. System for cell-based screening
US6576476B1 (en) 1998-09-02 2003-06-10 Ljl Biosystems, Inc. Chemiluminescence detection method and device
US20030127609A1 (en) * 1998-08-31 2003-07-10 Amer El-Hage Sample analysis systems
US20030137661A1 (en) * 2000-01-24 2003-07-24 Amnis Corporation Multipass cavity for illumination and excitation of moving objects
US20030138973A1 (en) * 1998-07-14 2003-07-24 Peter Wagner Microdevices for screening biomolecules
US20030142289A1 (en) * 2000-08-25 2003-07-31 Amnis Corporation Methods of calibrating an imaging system using calibration beads
US6638482B1 (en) 1993-11-01 2003-10-28 Nanogen, Inc. Reconfigurable detection and analysis apparatus and method
US20030207467A1 (en) * 2000-05-04 2003-11-06 Michael Snyder Protein chips for high throughput screening of protein activity
US6652808B1 (en) 1991-11-07 2003-11-25 Nanotronics, Inc. Methods for the electronic assembly and fabrication of devices
US6671624B1 (en) 1997-02-27 2003-12-30 Cellomics, Inc. Machine readable storage media for detecting distribution of macromolecules between nucleus and cytoplasm in cells
US6682942B1 (en) 1998-07-14 2004-01-27 Zyomyx, Inc. Microdevices for screening biomolecules
US20040021868A1 (en) * 1999-01-25 2004-02-05 Ortyn William E. Imaging and analyzing parameters of small moving objects such as cells
US20040029259A1 (en) * 2002-04-26 2004-02-12 Mcdevitt John T. Method and system for the detection of cardiac risk factors
US6706473B1 (en) 1996-12-06 2004-03-16 Nanogen, Inc. Systems and devices for photoelectrophoretic transport and hybridization of oligonucleotides
US6716588B2 (en) 1999-12-09 2004-04-06 Cellomics, Inc. System for cell-based screening
US20040077074A1 (en) * 1993-11-01 2004-04-22 Nanogen, Inc. Multi-chambered analysis device
US6726880B1 (en) 1993-11-01 2004-04-27 Nanogen, Inc. Electronic device for performing active biological operations and method of using same
US6727071B1 (en) 1997-02-27 2004-04-27 Cellomics, Inc. System for cell-based screening
US20040080442A1 (en) * 2001-01-24 2004-04-29 Koji Asami Interleaving A/D conversion type waveform digitizer module and a test apparatus
US20040086917A1 (en) * 1995-09-27 2004-05-06 Nanogen, Inc. Methods for electronic fluorescent perturbation for analysis and electronic perturbation catalysis for synthesis
US6746864B1 (en) 1994-08-08 2004-06-08 Science Applications International Corporation Automated system for simultaneously performing a plurality of signal-based assays
US6763149B2 (en) 2001-04-25 2004-07-13 Amnis Corporation Method and apparatus for correcting crosstalk and spatial resolution for multichannel imaging
US20040146880A1 (en) * 2002-07-26 2004-07-29 Nanogen, Inc. Methods and apparatus for screening and detecting multiple genetic mutations
US6780582B1 (en) 1998-07-14 2004-08-24 Zyomyx, Inc. Arrays of protein-capture agents and methods of use thereof
US20040175821A1 (en) * 2003-03-07 2004-09-09 Ehman Michael F. Integrated photodetector for heavy metals and biological activity analysis
US20040217256A1 (en) * 2000-08-25 2004-11-04 Amnis Corporation Auto focus for a flow imaging system
US20040218184A1 (en) * 1999-01-25 2004-11-04 Amnis Corporation Imaging platform for nanoparticle detection applied to SPR biomolecular interaction analysis
US6814934B1 (en) 1991-05-02 2004-11-09 Russell Gene Higuchi Instrument for monitoring nucleic acid amplification
US6825921B1 (en) 1999-11-10 2004-11-30 Molecular Devices Corporation Multi-mode light detection system
US20040239922A1 (en) * 1997-09-20 2004-12-02 Modlin Douglas N. Broad range light detection system
US20050053949A1 (en) * 2003-09-08 2005-03-10 Silin Vitalii Ivanovich Biochip for proteomics applications
US6872522B1 (en) 1996-06-25 2005-03-29 Michael Mecklenburg Broad specificity affinity arrays: a qualitative approach to complex sample discrimination
US20050118706A1 (en) * 1989-06-07 2005-06-02 Affymetrix, Inc. Polymer arrays
US20050118665A1 (en) * 2003-06-09 2005-06-02 Zhou Fang X. Methods for conducting assays for enzyme activity on protein microarrays
EP1544602A1 (en) * 2003-12-19 2005-06-22 STMicroelectronics Limited Bio-optical sensors
US20050164320A1 (en) * 1998-07-16 2005-07-28 Board Of Regents, The University Of Texas System Fluid based analysis of multiple analytes by a sensor array
US20050170495A1 (en) * 2002-05-16 2005-08-04 Applera Corporation Lens assembly for biological testing
US6947128B2 (en) 2000-08-25 2005-09-20 Amnis Corporation Alternative detector configuration and mode of operation of a time delay integration particle analyzer
US20050214863A1 (en) * 2003-12-11 2005-09-29 Mcdevitt John T Method and system for the analysis of saliva using a sensor array
US20050233473A1 (en) * 2002-08-16 2005-10-20 Zyomyx, Inc. Methods and reagents for surface functionalization
US20060000722A1 (en) * 1996-06-28 2006-01-05 Caliper Life Sciences, Inc. High throughput screening assay systems in microscale fluidic devices
US20060006344A1 (en) * 2002-05-16 2006-01-12 Applera Corporation Achromatic lens array
US20060065531A1 (en) * 2004-09-23 2006-03-30 Nanogen, Inc Methods and materials for optimization of electronic transportation and hybridization reactions
US20060068371A1 (en) * 1999-01-25 2006-03-30 Amnis Corporation Methods for analyzing inter-cellular phenomena
US20060073593A1 (en) * 2001-02-07 2006-04-06 Invitrogen Corporation Compositions and methods for molecular biology
US20060084106A1 (en) * 1993-10-28 2006-04-20 Beattie Kenneth L Microfabricated, flowthrough porous apparatus for discrete detection of binding reactions
US7101661B1 (en) 1993-11-01 2006-09-05 Nanogen, Inc. Apparatus for active programmable matrix devices
US7117098B1 (en) 1997-02-27 2006-10-03 Cellomics, Inc. Machine-readable storage medium for analyzing distribution of macromolecules between the cell membrane and the cell cytoplasm
US7122321B2 (en) 1997-11-12 2006-10-17 Johnson & Johnson Pharmaceutical Research & Development, L.L.C. High throughput method for functionally classifying proteins identified using a genomics approach
US20060257884A1 (en) * 2004-05-20 2006-11-16 Amnis Corporation Methods for preparing and analyzing cells having chromosomal abnormalities
US20060257993A1 (en) * 2004-02-27 2006-11-16 Mcdevitt John T Integration of fluids and reagents into self-contained cartridges containing sensor elements
US20060257992A1 (en) * 2004-02-27 2006-11-16 Mcdevitt John T Integration of fluids and reagents into self-contained cartridges containing sensor elements and reagent delivery systems
US20060291706A1 (en) * 2005-06-23 2006-12-28 Applera Corporation Method of extracting intensity data from digitized image
US20070062813A1 (en) * 2005-09-20 2007-03-22 Erik Gentalen Electrophoresis standards, methods and kits
US20070099294A1 (en) * 2005-11-02 2007-05-03 The Ohio State University Research Foundation Materials and methods for cell-based assays
US20070116376A1 (en) * 2005-11-18 2007-05-24 Kolterman James C Image based correction for unwanted light signals in a specific region of interest
US20070138024A1 (en) * 2004-09-21 2007-06-21 Swanson Paul D Electrode based patterning of thin film self-assembled nanoparticles
US20070146873A1 (en) * 2005-12-09 2007-06-28 Amnis Corporation Extended depth of field imaging for high speed object analysis
US20070243593A1 (en) * 1998-06-10 2007-10-18 Kent State University Detection and amplification of ligands
US7314708B1 (en) 1998-08-04 2008-01-01 Nanogen, Inc. Method and apparatus for electronic synthesis of molecular structures
US20080026365A1 (en) * 2005-01-07 2008-01-31 Van Heerde Waander L Hemostasis assay
US20080047832A1 (en) * 1994-07-07 2008-02-28 Nanogen Integrated portable biological detection system
US20080227653A1 (en) * 1989-06-07 2008-09-18 Fodor Stephen P A Expression monitoring by hybridization to high density oligonucleotide arrays
US20080240539A1 (en) * 2004-03-16 2008-10-02 Amins Corporation Method For Imaging And Differential Analysis Of Cells
US20080300798A1 (en) * 2007-04-16 2008-12-04 Mcdevitt John T Cardibioindex/cardibioscore and utility of salivary proteome in cardiovascular diagnostics
US20080317325A1 (en) * 1999-01-25 2008-12-25 Amnis Corporation Detection of circulating tumor cells using imaging flow cytometry
US20090155891A1 (en) * 2006-03-06 2009-06-18 Yuichi Tamaoki Apparatus for detecting nucleic acid amplification product in real time
US20090156423A1 (en) * 2000-10-17 2009-06-18 Febit Ag Method and device for integrated synthesis and analysis of analytes on a support
US20090215646A1 (en) * 2005-07-01 2009-08-27 The Board Of Regents Of The University Of Texas Sy System and method of analyte detection using differential receptors
US7625697B2 (en) 1994-06-17 2009-12-01 The Board Of Trustees Of The Leland Stanford Junior University Methods for constructing subarrays and subarrays made thereby
US20100038559A1 (en) * 2008-04-08 2010-02-18 Gilbert Feke Apparatus and method for fluorescence measurements using spatially structured illumination
US7794946B1 (en) 1998-02-04 2010-09-14 Life Technologies Corporation Microarray and uses therefor
US20100232675A1 (en) * 1999-01-25 2010-09-16 Amnis Corporation Blood and cell analysis using an imaging flow cytometer
US20100239137A1 (en) * 2007-10-09 2010-09-23 Siemens Healthcare Diagnostics Inc. Two Dimensional Imaging of Reacted Areas On a Reagent
US20100291588A1 (en) * 2005-06-24 2010-11-18 The Board Of Regents Of The University Of Texas System Systems and methods including self-contained cartridges with detection systems and fluid delivery systems
US7889263B2 (en) 2000-10-12 2011-02-15 Amnis Corporation System and method for high numeric aperture imaging systems
US20110085221A1 (en) * 2009-09-29 2011-04-14 Amnis Corporation Modifying the output of a laser to achieve a flat top in the laser's gaussian beam intensity profile
US20110132761A1 (en) * 2004-07-19 2011-06-09 Cell Biosciences, Inc. Methods and devices for analyte detection
US20110223605A1 (en) * 2009-06-04 2011-09-15 Lockheed Martin Corporation Multiple-sample microfluidic chip for DNA analysis
US8150136B2 (en) 2004-03-16 2012-04-03 Amnis Corporation Image based quantitation of molecular translocation
US8377398B2 (en) 2005-05-31 2013-02-19 The Board Of Regents Of The University Of Texas System Methods and compositions related to determination and use of white blood cell counts
US8817115B1 (en) 2010-05-05 2014-08-26 Amnis Corporation Spatial alignment of image data from a multichannel detector using a reference image
US8885913B2 (en) 1999-01-25 2014-11-11 Amnis Corporation Detection of circulating tumor cells using imaging flow cytometry
US8926905B2 (en) 2004-06-07 2015-01-06 Fluidigm Corporation Optical lens system and method for microfluidic devices
US8953866B2 (en) 2004-03-16 2015-02-10 Amnis Corporation Method for imaging and differential analysis of cells
US8961764B2 (en) 2010-10-15 2015-02-24 Lockheed Martin Corporation Micro fluidic optic design
US20150056097A1 (en) * 2013-08-23 2015-02-26 Aptina Imaging Corporation Imaging devices for molecule detection
US9069358B2 (en) 2013-06-24 2015-06-30 Biolytic Lab Performance, Inc. System for controlling and optimizing reactions in solid phase synthesis of small molecules
US9304133B2 (en) 2004-07-19 2016-04-05 ProteinSimple Methods and devices for analyte detection
US9322054B2 (en) 2012-02-22 2016-04-26 Lockheed Martin Corporation Microfluidic cartridge
US9766206B2 (en) 2013-09-27 2017-09-19 ProteinSimple Apparatus, systems, and methods for capillary electrophoresis
US9804079B2 (en) 2012-04-19 2017-10-31 ProteinSimple Dual wavelength isoelectric focusing for determining drug load in antibody drug conjugates
US10107782B2 (en) 2008-01-25 2018-10-23 ProteinSimple Method to perform limited two dimensional separation of proteins and other biologicals
US20210229092A1 (en) * 2019-03-11 2021-07-29 Beijing Boe Optoelectronics Technology Co., Ltd. Microfluidic chip and detection method using microfluidic chip
US11933759B2 (en) 2017-09-18 2024-03-19 ProteinSimple Apparatus, systems, and methods for capillary electrophoresis

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3951552A (en) * 1972-08-07 1976-04-20 Massachusetts Institute Of Technology Photometer-digitizer system
US4070578A (en) * 1976-07-30 1978-01-24 Timothy John G Detector array and method
US4476231A (en) * 1981-07-22 1984-10-09 International Remote Imaging Systems, Inc. Method of analyzing the distribution of a reagent between particles and liquid in a suspension
US4555731A (en) * 1984-04-30 1985-11-26 Polaroid Corporation Electronic imaging camera with microchannel plate
US4591570A (en) * 1983-02-02 1986-05-27 Centocor, Inc. Matrix of antibody-coated spots for determination of antigens

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3951552A (en) * 1972-08-07 1976-04-20 Massachusetts Institute Of Technology Photometer-digitizer system
US4070578A (en) * 1976-07-30 1978-01-24 Timothy John G Detector array and method
US4476231A (en) * 1981-07-22 1984-10-09 International Remote Imaging Systems, Inc. Method of analyzing the distribution of a reagent between particles and liquid in a suspension
US4591570A (en) * 1983-02-02 1986-05-27 Centocor, Inc. Matrix of antibody-coated spots for determination of antigens
US4555731A (en) * 1984-04-30 1985-11-26 Polaroid Corporation Electronic imaging camera with microchannel plate

Cited By (411)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5432099A (en) * 1987-08-06 1995-07-11 Multilyte Limited Determination of ambient concentation of several analytes
US6747143B2 (en) 1989-06-07 2004-06-08 Affymetrix, Inc. Methods for polymer synthesis
US6355432B1 (en) 1989-06-07 2002-03-12 Affymetrix Lnc. Products for detecting nucleic acids
US6660234B2 (en) 1989-06-07 2003-12-09 Affymetrix, Inc. Apparatus for polymer synthesis
US20030235853A1 (en) * 1989-06-07 2003-12-25 Affymetrix, Inc. Very large scale immobilized polymer synthesis
US20050079529A1 (en) * 1989-06-07 2005-04-14 Affymetrix, Inc. Very large scale immobilized polymer synthesis
US20050214828A1 (en) * 1989-06-07 2005-09-29 Affymetrix, Inc. Very large scale immobilized polymer synthesis
US20050208537A1 (en) * 1989-06-07 2005-09-22 Affymetrix, Inc. Very large scale immobilized polymer synthesis
US6646243B2 (en) 1989-06-07 2003-11-11 Affymetrix, Inc. Nucleic acid reading and analysis system
US20020137096A1 (en) * 1989-06-07 2002-09-26 Affymetrix, Inc. Apparatus comprising polymers
US6491871B1 (en) 1989-06-07 2002-12-10 Affymetrix, Inc. System for determining receptor-ligand binding affinity
US6630308B2 (en) 1989-06-07 2003-10-07 Affymetrix, Inc. Methods of synthesizing a plurality of different polymers on a surface of a substrate
US20050009014A9 (en) * 1989-06-07 2005-01-13 Affymetrix, Inc. Arrays for detecting nucleic acids
US20080227653A1 (en) * 1989-06-07 2008-09-18 Fodor Stephen P A Expression monitoring by hybridization to high density oligonucleotide arrays
US20020192684A1 (en) * 1989-06-07 2002-12-19 Affymetrix, Inc. Arrays for detecting nucleic acids
US20050170340A9 (en) * 1989-06-07 2005-08-04 Affymetrix, Inc. Arrays for detecting nucleic acids
US20050153363A1 (en) * 1989-06-07 2005-07-14 Pirrung Michael C. Polymer arrays
US20050153362A1 (en) * 1989-06-07 2005-07-14 Pirrung Michael C. Polymer arrays
US6440667B1 (en) 1989-06-07 2002-08-27 Affymetrix Inc. Analysis of target molecules using an encoding system
US6610482B1 (en) 1989-06-07 2003-08-26 Affymetrix, Inc. Support bound probes and methods of analysis using the same
US20030003475A1 (en) * 1989-06-07 2003-01-02 Affymetrix, Inc. Arrays for detecting nucleic acids
US20050148027A1 (en) * 1989-06-07 2005-07-07 Affymetrix Inc. Very large scale immobilized polymer synthesis
US20030119008A1 (en) * 1989-06-07 2003-06-26 Affymetrix, Inc. Nucleotides and analogs having photoremovable protecting groups
US20030119011A1 (en) * 1989-06-07 2003-06-26 Affymetrix, Inc. Arrays for detecting nucleic acids
US6416952B1 (en) 1989-06-07 2002-07-09 Affymetrix, Inc. Photolithographic and other means for manufacturing arrays
US6551784B2 (en) 1989-06-07 2003-04-22 Affymetrix Inc Method of comparing nucleic acid sequences
US20050118706A1 (en) * 1989-06-07 2005-06-02 Affymetrix, Inc. Polymer arrays
US20030108899A1 (en) * 1989-06-07 2003-06-12 Affymetrix, Inc. Very large scale immobilized polymer synthesis
US20040038268A1 (en) * 1989-06-07 2004-02-26 Affymetrix, Inc. Support bound probes and methods of analysis using the same
US6379895B1 (en) 1989-06-07 2002-04-30 Affymetrix, Inc. Photolithographic and other means for manufacturing arrays
US6403320B1 (en) 1989-06-07 2002-06-11 Affymetrix, Inc. Support bound probes and methods of analysis using the same
US6566495B1 (en) 1989-06-07 2003-05-20 Affymetrix, Inc. Very large scale immobilized polymer synthesis
US6403957B1 (en) 1989-06-07 2002-06-11 Affymetrix, Inc. Nucleic acid reading and analysis system
US20020155492A1 (en) * 1990-12-06 2002-10-24 Affymetrix, Inc. Arrays for detecting nucleic acids
US20040067521A1 (en) * 1990-12-06 2004-04-08 Affymetrix, Inc. Arrays for detecting nucleic acids
US20040248147A1 (en) * 1990-12-06 2004-12-09 Affymetrix, Inc. Arrays for detecting nucleic acids
US6814934B1 (en) 1991-05-02 2004-11-09 Russell Gene Higuchi Instrument for monitoring nucleic acid amplification
US6048690A (en) * 1991-11-07 2000-04-11 Nanogen, Inc. Methods for electronic fluorescent perturbation for analysis and electronic perturbation catalysis for synthesis
US6569382B1 (en) 1991-11-07 2003-05-27 Nanogen, Inc. Methods apparatus for the electronic, homogeneous assembly and fabrication of devices
US6652808B1 (en) 1991-11-07 2003-11-25 Nanotronics, Inc. Methods for the electronic assembly and fabrication of devices
US5653939A (en) * 1991-11-19 1997-08-05 Massachusetts Institute Of Technology Optical and electrical methods and apparatus for molecule detection
US5846708A (en) * 1991-11-19 1998-12-08 Massachusetts Institiute Of Technology Optical and electrical methods and apparatus for molecule detection
US5670113A (en) * 1991-12-20 1997-09-23 Sibia Neurosciences, Inc. Automated analysis equipment and assay method for detecting cell surface protein and/or cytoplasmic receptor function using same
US6372183B1 (en) 1991-12-20 2002-04-16 Merck & Co., Inc. Automated analysis equipment and assay method for detecting cell surface protein and/or cytoplasmic receptor function using same
US6057114A (en) * 1991-12-20 2000-05-02 Sibia Neurosciences, Inc. Automated assays and methods for detecting and modulating cell surface protein function
US5340747A (en) * 1992-03-09 1994-08-23 Difco Laboratories, Inc. Diagnostic microbiological testing apparatus and method
US5374892A (en) * 1993-03-04 1994-12-20 Georgia Tech Research Corporation Digital electrochemical instrument with background compensation
US5447687A (en) * 1993-03-19 1995-09-05 Lewis; Scott C. Luminometer
US6979567B2 (en) 1993-05-18 2005-12-27 Biocentrex, Llc Apparatus and methods for multi-analyte homogeneous fluoro-immunoassays
US6316274B1 (en) 1993-05-18 2001-11-13 University Of Utah Research Foundation Apparatus and methods for multi-analyte homogeneous fluoro-immunoassays
US5677196A (en) * 1993-05-18 1997-10-14 University Of Utah Research Foundation Apparatus and methods for multi-analyte homogeneous fluoro-immunoassays
US5919712A (en) * 1993-05-18 1999-07-06 University Of Utah Research Foundation Apparatus and methods for multi-analyte homogeneous fluoro-immunoassays
US5413939A (en) * 1993-06-29 1995-05-09 First Medical, Inc. Solid-phase binding assay system for interferometrically measuring analytes bound to an active receptor
US5595708A (en) * 1993-08-27 1997-01-21 Becton Dickinson And Company System for detecting bacterial growth in a plurality of culture vials
US7125674B2 (en) 1993-10-28 2006-10-24 Ut-Battelle, Llc Microfabricated flowthrough porous apparatus for discrete detection binding reactions
US20060084106A1 (en) * 1993-10-28 2006-04-20 Beattie Kenneth L Microfabricated, flowthrough porous apparatus for discrete detection of binding reactions
US20070178516A1 (en) * 1993-11-01 2007-08-02 Nanogen, Inc. Self-addressable self-assembling microelectronic integrated systems, component devices, mechanisms, methods, and procedures for molecular biological analysis and diagnostics
US5605662A (en) * 1993-11-01 1997-02-25 Nanogen, Inc. Active programmable electronic devices for molecular biological analysis and diagnostics
US6638482B1 (en) 1993-11-01 2003-10-28 Nanogen, Inc. Reconfigurable detection and analysis apparatus and method
US6375899B1 (en) 1993-11-01 2002-04-23 Nanogen, Inc. Electrophoretic buss for transport of charged materials in a multi-chamber system
US6245508B1 (en) 1993-11-01 2001-06-12 Nanogen, Inc. Method for fingerprinting utilizing an electronically addressable array
US6309602B1 (en) 1993-11-01 2001-10-30 Nanogen, Inc. Stacked, reconfigurable system for electrophoretic transport of charged materials
US6309601B1 (en) 1993-11-01 2001-10-30 Nanogen, Inc. Scanning optical detection system
WO1995012808A1 (en) * 1993-11-01 1995-05-11 Nanogen, Inc. Self-addressable self-assembling microelectronic systems and devices for molecular biological analysis and diagnostics
US8389212B1 (en) 1993-11-01 2013-03-05 Gamida For Life, B.V. Method for the electronic analysis of a sample oligonucleotide sequence
US6238624B1 (en) 1993-11-01 2001-05-29 Nanogen, Inc. Methods for transport in molecular biological analysis and diagnostics
US6315953B1 (en) 1993-11-01 2001-11-13 Nanogen, Inc. Devices for molecular biological analysis and diagnostics including waveguides
US6319472B1 (en) 1993-11-01 2001-11-20 Nanogen, Inc. System including functionally separated regions in electrophoretic system
US7425308B2 (en) 1993-11-01 2008-09-16 Nanogen, Inc. Systems for the active electronic control of biological reactions
US7704726B2 (en) 1993-11-01 2010-04-27 Gamida For Life B.V. Active programmable matrix devices
US6225059B1 (en) 1993-11-01 2001-05-01 Nanogen, Inc. Advanced active electronic devices including collection electrodes for molecular biological analysis and diagnostics
US20040077074A1 (en) * 1993-11-01 2004-04-22 Nanogen, Inc. Multi-chambered analysis device
US6331274B1 (en) 1993-11-01 2001-12-18 Nanogen, Inc. Advanced active circuits and devices for molecular biological analysis and diagnostics
US6821729B2 (en) 1993-11-01 2004-11-23 Nanogen, Inc. Devices for molecular biological analysis and diagnostics including waveguides
US6726880B1 (en) 1993-11-01 2004-04-27 Nanogen, Inc. Electronic device for performing active biological operations and method of using same
US6582660B1 (en) 1993-11-01 2003-06-24 Nanogen, Inc. Control system for active programmable electronic microbiology system
US20080203502A1 (en) * 1993-11-01 2008-08-28 Heller Michael J Self-addressable self-assembling microelectronic systems and devices for molecular biological analysis and diagnostics
US6254827B1 (en) 1993-11-01 2001-07-03 Nanogen, Inc. Methods for fabricating multi-component devices for molecular biological analysis and diagnostics
US20030190632A1 (en) * 1993-11-01 2003-10-09 Nanogen, Inc. Method for enhancing the hybridization efficiency of target nucleic acids using a self-addressable, self-assembling microelectronic device
US6287517B1 (en) 1993-11-01 2001-09-11 Nanogen, Inc. Laminated assembly for active bioelectronic devices
US20020028503A1 (en) * 1993-11-01 2002-03-07 Nanogen, Inc. Devices for molecular biological analysis and diagnostics including waveguides
US7858034B2 (en) 1993-11-01 2010-12-28 Gamida For Life B.V. Circuits for the control of output current in an electronic device for performing active biological operations
US7172864B1 (en) 1993-11-01 2007-02-06 Nanogen Methods for electronically-controlled enzymatic reactions
US6068818A (en) * 1993-11-01 2000-05-30 Nanogen, Inc. Multicomponent devices for molecular biological analysis and diagnostics
US6051380A (en) * 1993-11-01 2000-04-18 Nanogen, Inc. Methods and procedures for molecular biological analysis and diagnostics
US6017696A (en) * 1993-11-01 2000-01-25 Nanogen, Inc. Methods for electronic stringency control for molecular biological analysis and diagnostics
US5929208A (en) * 1993-11-01 1999-07-27 Nanogen, Inc. Methods for electronic synthesis of polymers
US20030073122A1 (en) * 1993-11-01 2003-04-17 Nanogen, Inc. Methods for determination of single nucleic acid polymorphisms using a bioelectronic microchip
US8313940B2 (en) 1993-11-01 2012-11-20 Gamida For Life B.V. Self-addressable self-assembling microelectronic systems and devices for molecular biological analysis and diagnostics
US6423271B1 (en) 1993-11-01 2002-07-23 Nanogen, Inc. Laminated assembly for active bioelectronic devices
US6540961B1 (en) 1993-11-01 2003-04-01 Nanogen, Inc. Multicomponent devices for molecular biological analysis and diagnostics
US20030059929A1 (en) * 1993-11-01 2003-03-27 Nanogen, Inc. Methods for electronic synthesis of complex structures
US6518022B1 (en) 1993-11-01 2003-02-11 Nanogen, Inc. Method for enhancing the hybridization efficiency of target nucleic acids using a self-addressable, self-assembling microelectronic device
US7101661B1 (en) 1993-11-01 2006-09-05 Nanogen, Inc. Apparatus for active programmable matrix devices
US5849486A (en) * 1993-11-01 1998-12-15 Nanogen, Inc. Methods for hybridization analysis utilizing electrically controlled hybridization
US7241419B2 (en) 1993-11-01 2007-07-10 Nanogen, Inc. Circuits for the control of output current in an electronic device for performing active biological operations
US7582421B2 (en) 1993-11-01 2009-09-01 Nanogen, Inc. Methods for determination of single nucleic acid polymorphisms using a bioelectronic microchip
US8114589B2 (en) 1993-11-01 2012-02-14 Gamida For Life B.V. Self-addressable self-assembling microelectronic integrated systems, component devices, mechanisms, methods, and procedures for molecular biological analysis and diagnostics
US5632957A (en) * 1993-11-01 1997-05-27 Nanogen Molecular biological diagnostic systems including electrodes
US5837551A (en) * 1993-12-24 1998-11-17 Ekins; Roger P. Binding assay
US7625697B2 (en) 1994-06-17 2009-12-01 The Board Of Trustees Of The Leland Stanford Junior University Methods for constructing subarrays and subarrays made thereby
US7947486B2 (en) 1994-07-07 2011-05-24 Gamida For Life B.V. Self-addressable self-assembling microelectronic systems and devices for molecular biological analysis and diagnostics
WO1996001836A1 (en) * 1994-07-07 1996-01-25 Nanogen, Inc. Self-addressable self-assembling microelectronic systems and devices for molecular biological analysis and diagnostics
US6403367B1 (en) 1994-07-07 2002-06-11 Nanogen, Inc. Integrated portable biological detection system
US20020155586A1 (en) * 1994-07-07 2002-10-24 Nanogen, Inc. Integrated portable biological detection system
US20080047832A1 (en) * 1994-07-07 2008-02-28 Nanogen Integrated portable biological detection system
US7857957B2 (en) 1994-07-07 2010-12-28 Gamida For Life B.V. Integrated portable biological detection system
US20020119484A1 (en) * 1994-07-07 2002-08-29 Nanogen, Inc. Primer extension detection methods on active electronic microarrays
US7172896B2 (en) 1994-07-07 2007-02-06 Nanogen, Inc. Integrated portable biological detection system
US6746864B1 (en) 1994-08-08 2004-06-08 Science Applications International Corporation Automated system for simultaneously performing a plurality of signal-based assays
US6800452B1 (en) 1994-08-08 2004-10-05 Science Applications International Corporation Automated methods for simultaneously performing a plurality of signal-based assays
US7427380B2 (en) 1994-08-08 2008-09-23 Science Applications International Corporation Automated system and method for simultaneously performing a plurality of signal-based assays
WO1996007917A1 (en) * 1994-09-09 1996-03-14 Nanogen, Inc. Automated molecular biological diagnostic system
US5981202A (en) * 1994-11-15 1999-11-09 Biosensor Laboratories Co., Ltd. Two-dimensional solid phase assay
US5686046A (en) * 1995-07-13 1997-11-11 Chiron Diagnostics Corporation Luminometer
US20040086917A1 (en) * 1995-09-27 2004-05-06 Nanogen, Inc. Methods for electronic fluorescent perturbation for analysis and electronic perturbation catalysis for synthesis
US6113886A (en) 1996-02-06 2000-09-05 Bruce Bryan Bioluminescent novelty items
US6152358A (en) 1996-02-06 2000-11-28 Bruce Bryan Bioluminescent novelty items
US20060053505A1 (en) * 1996-02-06 2006-03-09 Bruce Bryan Bioluminescent novelty items
US20020090665A1 (en) * 1996-04-16 2002-07-11 Caliper Technologies Corp. High throughput screening assay systems in microscale fluidic devices
US20020039751A1 (en) * 1996-04-16 2002-04-04 Caliper Technologies Corp. High throughput screening assay systems in microscale fluidic devices
US6849458B2 (en) 1996-05-09 2005-02-01 Michael W. Pantoliano Microplate thermal shift assay apparatus for ligand development and multi-variable protein chemistry optimization
US6268218B1 (en) 1996-05-09 2001-07-31 3-Dimensional Pharmaceuticals, Inc. Method for sensing and processing fluorescence data from multiple samples
US20040185504A1 (en) * 1996-05-09 2004-09-23 Pantoliano Michael W. Microplate thermal shift assay apparatus for ligand development and multi-variable protein chemistry optimization
WO1997045730A1 (en) * 1996-05-30 1997-12-04 Biodx Miniaturized cell array methods and apparatus for cell-based screening
US6103479A (en) * 1996-05-30 2000-08-15 Cellomics, Inc. Miniaturized cell array methods and apparatus for cell-based screening
US7662560B2 (en) 1996-06-25 2010-02-16 Michael Mecklenburg Broad specificity affinity arrays: a qualitative approach to complex sample discrimination
US6872522B1 (en) 1996-06-25 2005-03-29 Michael Mecklenburg Broad specificity affinity arrays: a qualitative approach to complex sample discrimination
US20050164274A1 (en) * 1996-06-25 2005-07-28 Michael Mecklenburg Broad specificity affinity arrays: a qualitative approach to complex sample discrimination
US20110111973A1 (en) * 1996-06-25 2011-05-12 Michael Mecklenburg Broad specificity affinity arrays: a qualitative approach to complex sample discrimination
US20040028567A1 (en) * 1996-06-28 2004-02-12 Caliper Technologies Corp. High throughput screening assay systems in microscale fluidic devices
US6267858B1 (en) * 1996-06-28 2001-07-31 Caliper Technologies Corp. High throughput screening assay systems in microscale fluidic devices
US6558960B1 (en) 1996-06-28 2003-05-06 Caliper Technologies Corp. High throughput screening assay systems in microscale fluidic devices
US6399389B1 (en) 1996-06-28 2002-06-04 Caliper Technologies Corp. High throughput screening assay systems in microscale fluidic devices
US20020168688A1 (en) * 1996-06-28 2002-11-14 Caliper Technologies Corp High throughput screening assay systems in microscale fluidic devices
US6413782B1 (en) 1996-06-28 2002-07-02 Caliper Technologies Corp. Methods of manufacturing high-throughput screening systems
US6274337B1 (en) 1996-06-28 2001-08-14 Caliper Technologies Corp. High throughput screening assay systems in microscale fluidic devices
US6150180A (en) * 1996-06-28 2000-11-21 Caliper Technologies Corp. High throughput screening assay systems in microscale fluidic devices
US7285411B1 (en) 1996-06-28 2007-10-23 Caliper Life Sciences, Inc. High throughput screening assay systems in microscale fluidic devices
US6630353B1 (en) 1996-06-28 2003-10-07 Caliper Technologies Corp. High throughput screening assay systems in microscale fluidic devices
US7091048B2 (en) 1996-06-28 2006-08-15 Parce J Wallace High throughput screening assay systems in microscale fluidic devices
US5942443A (en) * 1996-06-28 1999-08-24 Caliper Technologies Corporation High throughput screening assay systems in microscale fluidic devices
US6306659B1 (en) 1996-06-28 2001-10-23 Caliper Technologies Corp. High throughput screening assay systems in microscale fluidic devices
US20030134431A1 (en) * 1996-06-28 2003-07-17 Caliper Technologies Corp. High throughput screening assay systems in microscale fluidic devices
US6558944B1 (en) * 1996-06-28 2003-05-06 Caliper Technologies Corp. High throughput screening assay systems in microscale fluidic devices
US20050241941A1 (en) * 1996-06-28 2005-11-03 Caliper Life Sciences, Inc. High throughput screening assay systems in microscale fluidic devices
US20060000722A1 (en) * 1996-06-28 2006-01-05 Caliper Life Sciences, Inc. High throughput screening assay systems in microscale fluidic devices
US6479299B1 (en) 1996-06-28 2002-11-12 Caliper Technologies Corp. Pre-disposed assay components in microfluidic devices and methods
US6429025B1 (en) * 1996-06-28 2002-08-06 Caliper Technologies Corp. High-throughput screening assay systems in microscale fluidic devices
US7041509B2 (en) 1996-06-28 2006-05-09 Caliper Life Sciences, Inc. High throughput screening assay systems in microscale fluidic devices
US20040115696A1 (en) * 1996-12-06 2004-06-17 Nanotronics, Inc. Affinity based self-assembly systems and devices for photonic and electronic applications
US6706473B1 (en) 1996-12-06 2004-03-16 Nanogen, Inc. Systems and devices for photoelectrophoretic transport and hybridization of oligonucleotides
AU741076B2 (en) * 1996-12-12 2001-11-22 Prolume, Ltd. Apparatus and method for detecting and identifying infectious agents
US6649357B2 (en) 1996-12-12 2003-11-18 Prolume, Ltd. Apparatus and method for detecting and identifying infectious agents
WO1998026277A3 (en) * 1996-12-12 1999-06-24 Prolume Ltd Apparatus and method for detecting and identifying infectious agents
US6458547B1 (en) 1996-12-12 2002-10-01 Prolume, Ltd. Apparatus and method for detecting and identifying infectious agents
US6649356B2 (en) 1996-12-12 2003-11-18 Prolume, Ltd. Apparatus and method for detecting and identifying infectious agents
WO1998026277A2 (en) * 1996-12-12 1998-06-18 Prolume, Ltd. Apparatus and method for detecting and identifying infectious agents
US5827748A (en) * 1997-01-24 1998-10-27 The United States Of America As Represented By The Secretary Of The Navy Chemical sensor using two-dimensional lens array
US7853409B2 (en) 1997-02-27 2010-12-14 Cellomics, Inc. System for cell-based screening
US7235373B2 (en) 1997-02-27 2007-06-26 Cellomics, Inc. System for cell-based screening
US6573039B1 (en) 1997-02-27 2003-06-03 Cellomics, Inc. System for cell-based screening
US7060445B1 (en) 1997-02-27 2006-06-13 Cellomics, Inc. System for cell-based screening
US6902883B2 (en) 1997-02-27 2005-06-07 R. Terry Dunlay System for cell-based screening
US6620591B1 (en) 1997-02-27 2003-09-16 Cellomics, Inc. System for cell-based screening
US6671624B1 (en) 1997-02-27 2003-12-30 Cellomics, Inc. Machine readable storage media for detecting distribution of macromolecules between nucleus and cytoplasm in cells
US20040009539A1 (en) * 1997-02-27 2004-01-15 Dunlay R. Terry System for cell-based screening
US6727071B1 (en) 1997-02-27 2004-04-27 Cellomics, Inc. System for cell-based screening
US20080040044A1 (en) * 1997-02-27 2008-02-14 Cellomics, Inc. System for cell-based screening
US7117098B1 (en) 1997-02-27 2006-10-03 Cellomics, Inc. Machine-readable storage medium for analyzing distribution of macromolecules between the cell membrane and the cell cytoplasm
US20040063162A1 (en) * 1997-02-27 2004-04-01 Cellomics, Inc. System for cell-based screening
US6499366B1 (en) 1997-07-16 2002-12-31 Ljl Biosystems, Inc. Sample feeder
US6469311B1 (en) 1997-07-16 2002-10-22 Molecular Devices Corporation Detection device for light transmitted from a sensed volume
US6025985A (en) * 1997-07-16 2000-02-15 Ljl Biosystems, Inc. Moveable control unit for high-throughput analyzer
US6033100A (en) * 1997-07-16 2000-03-07 Ljl Biosystems, Inc. Floating head assembly
US6071748A (en) * 1997-07-16 2000-06-06 Ljl Biosystems, Inc. Light detection device
US6187267B1 (en) 1997-07-16 2001-02-13 Ljl Biosystems, Inc. Chemiluminescence detection device
US6159425A (en) * 1997-07-16 2000-12-12 Ljl Biosystems, Inc. Sample transporter
US6313960B2 (en) 1997-07-16 2001-11-06 Ljl Biosystems, Inc. Optical filter holder assembly
US6992761B2 (en) 1997-09-20 2006-01-31 Molecular Devices Corporation Broad range light detection system
US20040239922A1 (en) * 1997-09-20 2004-12-02 Modlin Douglas N. Broad range light detection system
US20030039997A1 (en) * 1997-09-22 2003-02-27 Aventis Research And Technologies Gmbh & Co. Kg Pentopyranosyl nucleic acid arrays, and uses thereof
US7153955B2 (en) 1997-09-22 2006-12-26 Nanogen Recognomics Gmbh Pentopyranosyl nucleic acid arrays, and uses thereof
US6548021B1 (en) 1997-10-10 2003-04-15 President And Fellows Of Harvard College Surface-bound, double-stranded DNA protein arrays
WO1999019510A1 (en) * 1997-10-10 1999-04-22 President And Fellows Of Harvard College Surface-bound, double-stranded dna protein arrays
US6097025A (en) * 1997-10-31 2000-08-01 Ljl Biosystems, Inc. Light detection device having an optical-path switching mechanism
US7122321B2 (en) 1997-11-12 2006-10-17 Johnson & Johnson Pharmaceutical Research & Development, L.L.C. High throughput method for functionally classifying proteins identified using a genomics approach
US7794946B1 (en) 1998-02-04 2010-09-14 Life Technologies Corporation Microarray and uses therefor
US8012703B2 (en) 1998-02-04 2011-09-06 Life Technologies Corporation Microarrays and uses therefor
US8637264B2 (en) 1998-02-04 2014-01-28 Life Technologies Corporation Microarrays and uses therefor
US6498335B2 (en) 1998-02-20 2002-12-24 Ljl Biosystems, Inc. Broad range light detection system
US6326605B1 (en) 1998-02-20 2001-12-04 Ljl Biosystems, Inc. Broad range light detection system
US6436682B1 (en) 1998-03-27 2002-08-20 Prolume, Ltd. Luciferases, fluorescent proteins, nucleic acids encoding the luciferases and fluorescent proteins and the use thereof in diagnostics, high throughput screening and novelty items
US6232107B1 (en) 1998-03-27 2001-05-15 Bruce J. Bryan Luciferases, fluorescent proteins, nucleic acids encoding the luciferases and fluorescent proteins and the use thereof in diagnostics, high throughput screening and novelty items
US6297018B1 (en) 1998-04-17 2001-10-02 Ljl Biosystems, Inc. Methods and apparatus for detecting nucleic acid polymorphisms
US6084669A (en) * 1998-05-01 2000-07-04 Roche Diagnostics Corporation Fluorescent light measuring device and an apparatus wherein such a device is used
US20070243593A1 (en) * 1998-06-10 2007-10-18 Kent State University Detection and amplification of ligands
US8747780B2 (en) 1998-06-16 2014-06-10 Mcluen Design, Inc. Multi-well rotary synthesizer
US8147776B2 (en) 1998-06-16 2012-04-03 Mcluen Design, Inc. Multi-well rotary synthesizer
US7150998B2 (en) 1998-06-16 2006-12-19 Mcluen Design, Inc. Multi-well rotary synthesizer
US8158085B2 (en) 1998-06-16 2012-04-17 Mcluen Design, Inc. Multi-well rotary synthesizer
US7192558B2 (en) 1998-06-16 2007-03-20 Mcluen Design, Inc. Multi-well rotary synthesizer
US6811755B2 (en) 1998-06-16 2004-11-02 Mcluen Design, Inc. Multi-well rotary synthesizer
US20010000723A1 (en) * 1998-06-16 2001-05-03 Mcluen Gary R. Multi-well rotary synthesizer
US20010001035A1 (en) * 1998-06-16 2001-05-10 Northwest Engineering Inc. Multi-well rotary synthesizer
US20010051114A1 (en) * 1998-06-16 2001-12-13 Mcluen Gary R. Multi-well rotary synthesizer
US8404196B2 (en) 1998-06-16 2013-03-26 Mcluen Design, Inc. Multi-well rotary synthesizer
US20010007644A1 (en) * 1998-06-16 2001-07-12 Mcluen Gary R. Multi-well rotary synthesizer
US6270730B1 (en) 1998-06-16 2001-08-07 Northwest Engineering Inc. Multi-well rotary synthesizer
US20110086779A1 (en) * 1998-07-14 2011-04-14 Zyomyx, Inc. Arrays of protein capture agents and methods of use thereof
US20020110933A1 (en) * 1998-07-14 2002-08-15 Peter Wagner Arrays of proteins and methods of use thereof
US6475808B1 (en) * 1998-07-14 2002-11-05 Zyomyx, Incorporated Arrays of proteins and methods of use thereof
US20050100947A1 (en) * 1998-07-14 2005-05-12 Zyomyx, Inc. Array devices and methods of use thereof
US6897073B2 (en) 1998-07-14 2005-05-24 Zyomyx, Inc. Non-specific binding resistant protein arrays and methods for making the same
US20050014292A1 (en) * 1998-07-14 2005-01-20 Peter Wagner Protein arrays for high-throughput screening
US6630358B1 (en) * 1998-07-14 2003-10-07 Zyomyx, Incorporated Arrays of proteins and methods of use thereof
US6475809B1 (en) 1998-07-14 2002-11-05 Zyomyx, Incorporated Protein arrays for high-throughput screening
US20030138973A1 (en) * 1998-07-14 2003-07-24 Peter Wagner Microdevices for screening biomolecules
US6596545B1 (en) 1998-07-14 2003-07-22 Zyomyx, Inc. Microdevices for screening biomolecules
US6329209B1 (en) * 1998-07-14 2001-12-11 Zyomyx, Incorporated Arrays of protein-capture agents and methods of use thereof
US20050008674A1 (en) * 1998-07-14 2005-01-13 Peter Wagner Protein arrays for high-throughput screening
US6582969B1 (en) 1998-07-14 2003-06-24 Zyomyx, Inc. Microdevices for high-throughput screening of biomolecules
US6365418B1 (en) * 1998-07-14 2002-04-02 Zyomyx, Incorporated Arrays of protein-capture agents and methods of use thereof
US6576478B1 (en) 1998-07-14 2003-06-10 Zyomyx, Inc. Microdevices for high-throughput screening of biomolecules
US6780582B1 (en) 1998-07-14 2004-08-24 Zyomyx, Inc. Arrays of protein-capture agents and methods of use thereof
US6406921B1 (en) 1998-07-14 2002-06-18 Zyomyx, Incorporated Protein arrays for high-throughput screening
US20040241751A1 (en) * 1998-07-14 2004-12-02 Peter Wagner Arrays of protein-capture agents and methods of use thereof
US20020106702A1 (en) * 1998-07-14 2002-08-08 Peter Wagner Protein arrays for high-throughput screening
US6682942B1 (en) 1998-07-14 2004-01-27 Zyomyx, Inc. Microdevices for screening biomolecules
US20020110932A1 (en) * 1998-07-14 2002-08-15 Peter Wagner Microdevices for screening biomolecules
US20030003599A1 (en) * 1998-07-14 2003-01-02 Peter Wagner Arrays of protein-capture agents and methods of use thereof
US20020119579A1 (en) * 1998-07-14 2002-08-29 Peter Wagner Arrays devices and methods of use thereof
US20020132272A1 (en) * 1998-07-14 2002-09-19 Peter Wagner Non-specific binding resistant protein arrays and methods for making the same
US20050164320A1 (en) * 1998-07-16 2005-07-28 Board Of Regents, The University Of Texas System Fluid based analysis of multiple analytes by a sensor array
US20090258791A1 (en) * 1998-07-16 2009-10-15 Mcdevitt John T Fluid Based Analysis of Multiple Analytes by a Sensor Array
US7491552B2 (en) 1998-07-16 2009-02-17 The Board Of Regents Of The University Of Texas System Fluid based analysis of multiple analytes by a sensor array
US6466316B2 (en) 1998-07-27 2002-10-15 Ljl Biosystems, Inc. Apparatus and methods for spectroscopic measurements
US6483582B2 (en) 1998-07-27 2002-11-19 Ljl Biosystems, Inc. Apparatus and methods for time-resolved spectroscopic measurements
US7314708B1 (en) 1998-08-04 2008-01-01 Nanogen, Inc. Method and apparatus for electronic synthesis of molecular structures
US6132685A (en) * 1998-08-10 2000-10-17 Caliper Technologies Corporation High throughput microfluidic systems and methods
US7316801B2 (en) 1998-08-10 2008-01-08 Caliper Life Sciences, Inc. High throughput microfluidic systems and methods
US20030017085A1 (en) * 1998-08-10 2003-01-23 Caliper Technologies Corp. High throughput microfluidic systems and methods
US6495369B1 (en) 1998-08-10 2002-12-17 Caliper Technologies Corp. High throughput microfluidic systems and methods
US6271042B1 (en) * 1998-08-26 2001-08-07 Alpha Innotech Corporation Biochip detection system
US20010031502A1 (en) * 1998-08-26 2001-10-18 Watson Robert Malcolm Biochip detection system
US20030127609A1 (en) * 1998-08-31 2003-07-10 Amer El-Hage Sample analysis systems
US6576476B1 (en) 1998-09-02 2003-06-10 Ljl Biosystems, Inc. Chemiluminescence detection method and device
US20030175813A1 (en) * 1998-11-12 2003-09-18 3-Dimensional Pharmaceuticals, Inc. Microplate thermal shift assay for ligand development using 5- (4"-dimethylaminophenyl) -2- (4' -phenyl) oxazole derivative fluorescent dyes
US6569631B1 (en) 1998-11-12 2003-05-27 3-Dimensional Pharmaceuticals, Inc. Microplate thermal shift assay for ligand development using 5-(4″dimethylaminophenyl)-2-(4′-phenyl)oxazole derivative fluorescent dyes
US20090190822A1 (en) * 1999-01-25 2009-07-30 Amnis Corporation Blood and cell analysis using an imaging flow cytometer
US7634125B2 (en) 1999-01-25 2009-12-15 Amnis Corporation Blood and cell analysis using an imaging flow cytometer
US20060068371A1 (en) * 1999-01-25 2006-03-30 Amnis Corporation Methods for analyzing inter-cellular phenomena
US7057732B2 (en) 1999-01-25 2006-06-06 Amnis Corporation Imaging platform for nanoparticle detection applied to SPR biomolecular interaction analysis
US8009189B2 (en) 1999-01-25 2011-08-30 Amnis Corporation Extended depth of field imaging for high speed object analysis
US7221457B2 (en) 1999-01-25 2007-05-22 Amnis Corporation Imaging platform for nanoparticle detection applied to SPR biomolecular interaction analysis
US7925069B2 (en) 1999-01-25 2011-04-12 Amnis Corporation Blood and cell analysis using an imaging flow cytometer
US20060066837A1 (en) * 1999-01-25 2006-03-30 Amnis Corporation Imaging and analyzing parameters of small moving objects such as cells
US6947136B2 (en) 1999-01-25 2005-09-20 Amnis Corporation Multipass cavity for illumination and excitation of moving objects
US20060192955A1 (en) * 1999-01-25 2006-08-31 Amnis Corporation Imaging platform for nanoparticle detection applied to spr biomolecular interaction analysis
US8406498B2 (en) 1999-01-25 2013-03-26 Amnis Corporation Blood and cell analysis using an imaging flow cytometer
US20100232675A1 (en) * 1999-01-25 2010-09-16 Amnis Corporation Blood and cell analysis using an imaging flow cytometer
US20060204071A1 (en) * 1999-01-25 2006-09-14 Amnis Corporation Blood and cell analysis using an imaging flow cytometer
US6975400B2 (en) 1999-01-25 2005-12-13 Amnis Corporation Imaging and analyzing parameters of small moving objects such as cells
US20100021039A1 (en) * 1999-01-25 2010-01-28 Amnis Corporation Blood and cell analysis using an imaging flow cytometer
US8131053B2 (en) 1999-01-25 2012-03-06 Amnis Corporation Detection of circulating tumor cells using imaging flow cytometry
US7634126B2 (en) 1999-01-25 2009-12-15 Amnis Corporation Blood and cell analysis using an imaging flow cytometer
US8548219B2 (en) 1999-01-25 2013-10-01 Amnis Corporation Detection of circulating tumor cells using imaging flow cytometry
US7315357B2 (en) 1999-01-25 2008-01-01 Amnis Corporation Imaging and analyzing parameters of small moving objects such as cells
US7522758B2 (en) 1999-01-25 2009-04-21 Amnis Corporation Blood and cell analysis using an imaging flow cytometer
US20040021868A1 (en) * 1999-01-25 2004-02-05 Ortyn William E. Imaging and analyzing parameters of small moving objects such as cells
US20090003681A1 (en) * 1999-01-25 2009-01-01 Amnis Corporation Blood and cell analysis using an imaging flow cytometer
US20080317325A1 (en) * 1999-01-25 2008-12-25 Amnis Corporation Detection of circulating tumor cells using imaging flow cytometry
US7450229B2 (en) 1999-01-25 2008-11-11 Amnis Corporation Methods for analyzing inter-cellular phenomena
US20080234984A1 (en) * 1999-01-25 2008-09-25 Amnis Corporation Extended depth of field imaging for high speed object analysis
US20040080748A1 (en) * 1999-01-25 2004-04-29 Amnis Corporation Multipass cavity for illumination and excitation of moving objects
US20040218184A1 (en) * 1999-01-25 2004-11-04 Amnis Corporation Imaging platform for nanoparticle detection applied to SPR biomolecular interaction analysis
US8660332B2 (en) 1999-01-25 2014-02-25 Amnis Corporation Blood and cell analysis using an imaging flow cytometer
US8885913B2 (en) 1999-01-25 2014-11-11 Amnis Corporation Detection of circulating tumor cells using imaging flow cytometry
US6317207B2 (en) 1999-02-23 2001-11-13 Ljl Biosystems, Inc. Frequency-domain light detection device
US20030146095A1 (en) * 1999-11-08 2003-08-07 Nanogen, Inc. Methods for the electronic, Homogeneous assembly and fabrication of devices
US7060224B2 (en) 1999-11-08 2006-06-13 Nanogen, Inc. Methods for the electronic, homogeneous assembly and fabrication of devices
US6825921B1 (en) 1999-11-10 2004-11-30 Molecular Devices Corporation Multi-mode light detection system
US6716588B2 (en) 1999-12-09 2004-04-06 Cellomics, Inc. System for cell-based screening
US6707551B2 (en) 2000-01-24 2004-03-16 Amnis Corporation Multipass cavity for illumination and excitation of moving objects
US20030137661A1 (en) * 2000-01-24 2003-07-24 Amnis Corporation Multipass cavity for illumination and excitation of moving objects
US20030092098A1 (en) * 2000-03-15 2003-05-15 Bruce Bryan Renilla reniformis fluorescent proteins, nucleic acids encoding the fluorescent proteins and the use thereof in diagnostics, high throughput screening and novelty items
US7109315B2 (en) 2000-03-15 2006-09-19 Bruce J. Bryan Renilla reniformis fluorescent proteins, nucleic acids encoding the fluorescent proteins and the use thereof in diagnostics, high throughput screening and novelty items
US20050272111A1 (en) * 2000-03-15 2005-12-08 Bruce Bryan Renilla reniformis fluorescent proteins, nucleic acids encoding the fluorescent proteins and the use thereof in diagnostics, high throughput screening and novelty items
US8399383B2 (en) 2000-05-04 2013-03-19 Yale University Protein chips for high throughput screening of protein activity
US20030207467A1 (en) * 2000-05-04 2003-11-06 Michael Snyder Protein chips for high throughput screening of protein activity
US20040223135A1 (en) * 2000-08-25 2004-11-11 Amnis Corporation Methods of calibrating an imaging system using calibration beads
US20030142289A1 (en) * 2000-08-25 2003-07-31 Amnis Corporation Methods of calibrating an imaging system using calibration beads
US6906792B2 (en) 2000-08-25 2005-06-14 Amnis Corporation Methods of calibrating an imaging system using calibration beads
US6875973B2 (en) 2000-08-25 2005-04-05 Amnis Corporation Auto focus for a flow imaging system
US20050127271A1 (en) * 2000-08-25 2005-06-16 Amnis Corporation Auto focus for a flow imagin system
US6778263B2 (en) 2000-08-25 2004-08-17 Amnis Corporation Methods of calibrating an imaging system using calibration beads
US7567695B2 (en) 2000-08-25 2009-07-28 Amnis Corporation Method and apparatus for reading reporter labeled beads
US6934408B2 (en) 2000-08-25 2005-08-23 Amnis Corporation Method and apparatus for reading reporter labeled beads
US7087877B2 (en) 2000-08-25 2006-08-08 Amnis Corporation Auto focus for a flow imaging system
US20060029267A1 (en) * 2000-08-25 2006-02-09 Amnis Corporation Method and apparatus for reading reporter labeled beads
US20040217256A1 (en) * 2000-08-25 2004-11-04 Amnis Corporation Auto focus for a flow imaging system
US6947128B2 (en) 2000-08-25 2005-09-20 Amnis Corporation Alternative detector configuration and mode of operation of a time delay integration particle analyzer
US20020094116A1 (en) * 2000-08-25 2002-07-18 Amnis Corporation Method and apparatus for reading reporter labeled beads
US8379136B2 (en) 2000-10-12 2013-02-19 Amnis Corporation System and method for high numeric aperture imaging systems
US7889263B2 (en) 2000-10-12 2011-02-15 Amnis Corporation System and method for high numeric aperture imaging systems
US20090156423A1 (en) * 2000-10-17 2009-06-18 Febit Ag Method and device for integrated synthesis and analysis of analytes on a support
US20040080442A1 (en) * 2001-01-24 2004-04-29 Koji Asami Interleaving A/D conversion type waveform digitizer module and a test apparatus
US20060073593A1 (en) * 2001-02-07 2006-04-06 Invitrogen Corporation Compositions and methods for molecular biology
US20020146734A1 (en) * 2001-02-21 2002-10-10 Amnis Corporation Method and apparatus for labeling and analyzing cellular components
US7006710B2 (en) 2001-04-25 2006-02-28 Amnis Corporation Method and apparatus for correcting crosstalk and spatial resolution for multichannel imaging
US20060002634A1 (en) * 2001-04-25 2006-01-05 Amnis Corporation Method and apparatus for correcting crosstalk and spatial resolution for multichannel imaging
US20060198558A1 (en) * 2001-04-25 2006-09-07 Amnis Corporation Method and apparatus for correcting crosstalk and spatial resolution for multichannel imaging
US20040161165A1 (en) * 2001-04-25 2004-08-19 Amnis Corporation Method and apparatus for correcting crosstalk and spatial resolution for multichannel imaging
US7286719B2 (en) 2001-04-25 2007-10-23 Amnis Corporation Method and apparatus for correcting crosstalk and spatial resolution for multichannel imaging
US7079708B2 (en) 2001-04-25 2006-07-18 Amnis Corporation Method and apparatus for correcting crosstalk and spatial resolution for multichannel imaging
US6763149B2 (en) 2001-04-25 2004-07-13 Amnis Corporation Method and apparatus for correcting crosstalk and spatial resolution for multichannel imaging
US6618140B2 (en) 2001-06-18 2003-09-09 Amnis Corporation Spectral deconvolution of fluorescent markers
WO2002103335A1 (en) * 2001-06-18 2002-12-27 Amnis Corporation Spectral deconvolution of fluorescent markers
US20030086608A1 (en) * 2001-07-17 2003-05-08 Amnis Corporation Computational methods for the segmentation of images of objects from background in a flow imaging instrument
US7190832B2 (en) 2001-07-17 2007-03-13 Amnis Corporation Computational methods for the segmentation of images of objects from background in a flow imaging instrument
US8257967B2 (en) 2002-04-26 2012-09-04 Board Of Regents, The University Of Texas System Method and system for the detection of cardiac risk factors
US20040029259A1 (en) * 2002-04-26 2004-02-12 Mcdevitt John T. Method and system for the detection of cardiac risk factors
US20060006344A1 (en) * 2002-05-16 2006-01-12 Applera Corporation Achromatic lens array
US20050170495A1 (en) * 2002-05-16 2005-08-04 Applera Corporation Lens assembly for biological testing
US9157860B2 (en) 2002-05-16 2015-10-13 Applied Biosystems, Llc Achromatic lens array
US7407798B2 (en) * 2002-05-16 2008-08-05 Applera Corporation Lens assembly for biological testing
US9310301B2 (en) 2002-05-16 2016-04-12 Applied Biosystems, Llc Lens assembly for biological testing
US9448103B2 (en) 2002-05-16 2016-09-20 Applied Biosystems, Llc Achromatic lens array
US8772467B2 (en) 2002-07-26 2014-07-08 Gamida For Life B.V. Methods and apparatus for screening and detecting multiple genetic mutations
US20040146880A1 (en) * 2002-07-26 2004-07-29 Nanogen, Inc. Methods and apparatus for screening and detecting multiple genetic mutations
US20100167960A1 (en) * 2002-07-26 2010-07-01 Radtkey Ray R Methods and apparatus for screening and detecting multiple genetic mutations
US7601493B2 (en) 2002-07-26 2009-10-13 Nanogen, Inc. Methods and apparatus for screening and detecting multiple genetic mutations
US20050233473A1 (en) * 2002-08-16 2005-10-20 Zyomyx, Inc. Methods and reagents for surface functionalization
US20040175821A1 (en) * 2003-03-07 2004-09-09 Ehman Michael F. Integrated photodetector for heavy metals and biological activity analysis
US7635572B2 (en) 2003-06-09 2009-12-22 Life Technologies Corporation Methods for conducting assays for enzyme activity on protein microarrays
US20050118665A1 (en) * 2003-06-09 2005-06-02 Zhou Fang X. Methods for conducting assays for enzyme activity on protein microarrays
US20050053949A1 (en) * 2003-09-08 2005-03-10 Silin Vitalii Ivanovich Biochip for proteomics applications
US7651868B2 (en) 2003-12-11 2010-01-26 The Board Of Regents Of The University Of Texas System Method and system for the analysis of saliva using a sensor array
US20050214863A1 (en) * 2003-12-11 2005-09-29 Mcdevitt John T Method and system for the analysis of saliva using a sensor array
US7447385B2 (en) 2003-12-19 2008-11-04 Stmicroelectronics Ltd. Bio-optical sensors
US20050141058A1 (en) * 2003-12-19 2005-06-30 Stmicroelectronics Ltd. Bio-optical sensors
EP1544602A1 (en) * 2003-12-19 2005-06-22 STMicroelectronics Limited Bio-optical sensors
US20060257993A1 (en) * 2004-02-27 2006-11-16 Mcdevitt John T Integration of fluids and reagents into self-contained cartridges containing sensor elements
US20060257992A1 (en) * 2004-02-27 2006-11-16 Mcdevitt John T Integration of fluids and reagents into self-contained cartridges containing sensor elements and reagent delivery systems
US8105849B2 (en) 2004-02-27 2012-01-31 Board Of Regents, The University Of Texas System Integration of fluids and reagents into self-contained cartridges containing sensor elements
US8101431B2 (en) 2004-02-27 2012-01-24 Board Of Regents, The University Of Texas System Integration of fluids and reagents into self-contained cartridges containing sensor elements and reagent delivery systems
US8571294B2 (en) 2004-03-16 2013-10-29 Amnis Corporation Method for imaging and differential analysis of cells
US8150136B2 (en) 2004-03-16 2012-04-03 Amnis Corporation Image based quantitation of molecular translocation
US8824770B2 (en) 2004-03-16 2014-09-02 Amnis Corporation Method for imaging and differential analysis of cells
US20080240539A1 (en) * 2004-03-16 2008-10-02 Amins Corporation Method For Imaging And Differential Analysis Of Cells
US8103080B2 (en) 2004-03-16 2012-01-24 Amnis Corporation Method for imaging and differential analysis of cells
US8571295B2 (en) 2004-03-16 2013-10-29 Amnis Corporation Method for imaging and differential analysis of cells
US9528989B2 (en) 2004-03-16 2016-12-27 Amnis Corporation Image-based quantitation of molecular translocation
US8953866B2 (en) 2004-03-16 2015-02-10 Amnis Corporation Method for imaging and differential analysis of cells
US20060257884A1 (en) * 2004-05-20 2006-11-16 Amnis Corporation Methods for preparing and analyzing cells having chromosomal abnormalities
US9663821B2 (en) 2004-06-07 2017-05-30 Fluidigm Corporation Optical lens system and method for microfluidic devices
US9234237B2 (en) 2004-06-07 2016-01-12 Fluidigm Corporation Optical lens system and method for microfluidic devices
US8926905B2 (en) 2004-06-07 2015-01-06 Fluidigm Corporation Optical lens system and method for microfluidic devices
US10106846B2 (en) 2004-06-07 2018-10-23 Fluidigm Corporation Optical lens system and method for microfluidic devices
US10745748B2 (en) 2004-06-07 2020-08-18 Fluidigm Corporation Optical lens system and method for microfluidic devices
US9400277B2 (en) * 2004-07-19 2016-07-26 ProteinSimple Methods and devices for analyte detection
US9304133B2 (en) 2004-07-19 2016-04-05 ProteinSimple Methods and devices for analyte detection
US20110132761A1 (en) * 2004-07-19 2011-06-09 Cell Biosciences, Inc. Methods and devices for analyte detection
US7828954B2 (en) 2004-09-21 2010-11-09 Gamida For Life B.V. Electrode based patterning of thin film self-assembled nanoparticles
US20070138024A1 (en) * 2004-09-21 2007-06-21 Swanson Paul D Electrode based patterning of thin film self-assembled nanoparticles
US20060065531A1 (en) * 2004-09-23 2006-03-30 Nanogen, Inc Methods and materials for optimization of electronic transportation and hybridization reactions
US7314542B2 (en) 2004-09-23 2008-01-01 Nanogen, Inc. Methods and materials for optimization of electronic transportation and hybridization reactions
JP2008526219A (en) * 2005-01-07 2008-07-24 スティヒティング・カトリーケ・ユニフェルジテイト Hemostasis assay
US20080026365A1 (en) * 2005-01-07 2008-01-31 Van Heerde Waander L Hemostasis assay
US8809006B2 (en) 2005-01-07 2014-08-19 Stichting Katholieke Universiteit Hemostasis assay
JP4931826B2 (en) * 2005-01-07 2012-05-16 スティヒティング・カトリーケ・ユニフェルジテイト Hemostasis assay
EP1833982B1 (en) * 2005-01-07 2010-12-01 Stichting Katholieke Universiteit Hemostasis assay
US8377398B2 (en) 2005-05-31 2013-02-19 The Board Of Regents Of The University Of Texas System Methods and compositions related to determination and use of white blood cell counts
US20060291706A1 (en) * 2005-06-23 2006-12-28 Applera Corporation Method of extracting intensity data from digitized image
US20100291588A1 (en) * 2005-06-24 2010-11-18 The Board Of Regents Of The University Of Texas System Systems and methods including self-contained cartridges with detection systems and fluid delivery systems
US20090215646A1 (en) * 2005-07-01 2009-08-27 The Board Of Regents Of The University Of Texas Sy System and method of analyte detection using differential receptors
US8945361B2 (en) 2005-09-20 2015-02-03 ProteinSimple Electrophoresis standards, methods and kits
US20070062813A1 (en) * 2005-09-20 2007-03-22 Erik Gentalen Electrophoresis standards, methods and kits
US20070099294A1 (en) * 2005-11-02 2007-05-03 The Ohio State University Research Foundation Materials and methods for cell-based assays
US8603806B2 (en) * 2005-11-02 2013-12-10 The Ohio State Universtiy Research Foundation Materials and methods for cell-based assays
US20070116376A1 (en) * 2005-11-18 2007-05-24 Kolterman James C Image based correction for unwanted light signals in a specific region of interest
US8249381B2 (en) 2005-11-18 2012-08-21 Abbott Laboratories Image based correction for unwanted light signals in a specific region of interest
US8005314B2 (en) 2005-12-09 2011-08-23 Amnis Corporation Extended depth of field imaging for high speed object analysis
US20070146873A1 (en) * 2005-12-09 2007-06-28 Amnis Corporation Extended depth of field imaging for high speed object analysis
US10544453B2 (en) 2006-03-06 2020-01-28 Phc Holdings Corporation Method for detecting nucleic acid amplification product in real time
CN103232936A (en) * 2006-03-06 2013-08-07 松下健康医疗器械株式会社 Real-time detection apparatus of nucleic acid amplification product
CN103232936B (en) * 2006-03-06 2016-04-06 松下健康医疗控股株式会社 Apparatus for real-time detection of nucleic acid amplification product
US20090155891A1 (en) * 2006-03-06 2009-06-18 Yuichi Tamaoki Apparatus for detecting nucleic acid amplification product in real time
US20080300798A1 (en) * 2007-04-16 2008-12-04 Mcdevitt John T Cardibioindex/cardibioscore and utility of salivary proteome in cardiovascular diagnostics
US20100239137A1 (en) * 2007-10-09 2010-09-23 Siemens Healthcare Diagnostics Inc. Two Dimensional Imaging of Reacted Areas On a Reagent
US10107782B2 (en) 2008-01-25 2018-10-23 ProteinSimple Method to perform limited two dimensional separation of proteins and other biologicals
US20100038559A1 (en) * 2008-04-08 2010-02-18 Gilbert Feke Apparatus and method for fluorescence measurements using spatially structured illumination
US7994485B2 (en) 2008-04-08 2011-08-09 Carestream Health, Inc. Apparatus and method for fluorescence measurements using spatially structured illumination
US20110223605A1 (en) * 2009-06-04 2011-09-15 Lockheed Martin Corporation Multiple-sample microfluidic chip for DNA analysis
US9649631B2 (en) 2009-06-04 2017-05-16 Leidos Innovations Technology, Inc. Multiple-sample microfluidic chip for DNA analysis
US9656261B2 (en) 2009-06-04 2017-05-23 Leidos Innovations Technology, Inc. DNA analyzer
US9067207B2 (en) 2009-06-04 2015-06-30 University Of Virginia Patent Foundation Optical approach for microfluidic DNA electrophoresis detection
US20110085221A1 (en) * 2009-09-29 2011-04-14 Amnis Corporation Modifying the output of a laser to achieve a flat top in the laser's gaussian beam intensity profile
US8451524B2 (en) 2009-09-29 2013-05-28 Amnis Corporation Modifying the output of a laser to achieve a flat top in the laser's Gaussian beam intensity profile
US8817115B1 (en) 2010-05-05 2014-08-26 Amnis Corporation Spatial alignment of image data from a multichannel detector using a reference image
US8961764B2 (en) 2010-10-15 2015-02-24 Lockheed Martin Corporation Micro fluidic optic design
US9322054B2 (en) 2012-02-22 2016-04-26 Lockheed Martin Corporation Microfluidic cartridge
US9988676B2 (en) 2012-02-22 2018-06-05 Leidos Innovations Technology, Inc. Microfluidic cartridge
US10753859B2 (en) 2012-04-19 2020-08-25 ProteinSimple Dual wavelength isoelectric focusing for determining drug load in antibody drug conjugates
US9804079B2 (en) 2012-04-19 2017-10-31 ProteinSimple Dual wavelength isoelectric focusing for determining drug load in antibody drug conjugates
US9069358B2 (en) 2013-06-24 2015-06-30 Biolytic Lab Performance, Inc. System for controlling and optimizing reactions in solid phase synthesis of small molecules
US20150056097A1 (en) * 2013-08-23 2015-02-26 Aptina Imaging Corporation Imaging devices for molecule detection
US9683937B2 (en) * 2013-08-23 2017-06-20 Semiconductor Components Industries, Llc Imaging devices for molecule detection
US9766206B2 (en) 2013-09-27 2017-09-19 ProteinSimple Apparatus, systems, and methods for capillary electrophoresis
US11933759B2 (en) 2017-09-18 2024-03-19 ProteinSimple Apparatus, systems, and methods for capillary electrophoresis
US20210229092A1 (en) * 2019-03-11 2021-07-29 Beijing Boe Optoelectronics Technology Co., Ltd. Microfluidic chip and detection method using microfluidic chip

Similar Documents

Publication Publication Date Title
US5096807A (en) Imaging immunoassay detection system with background compensation and its use
EP0194132A2 (en) Imaging immunoassay detection system and method
US4922092A (en) High sensitivity optical imaging apparatus
US6263095B1 (en) Imaging method and apparatus
JP5551211B2 (en) Luminescence detection workstation
JP3448090B2 (en) Energy transfer detection method and apparatus
CN100465619C (en) Assay plates, reader systems and methods for luminescence test measurements
JP4663824B2 (en) Multiplexed molecular analyzer and method
US4626684A (en) Rapid and automatic fluorescence immunoassay analyzer for multiple micro-samples
US20030157581A1 (en) Use of an imaging photoelectric flat sensor for evaluating biochips and imaging method therefor
US6730521B1 (en) Chemical and biochemical assay method and apparatus
US5945344A (en) Electrochemiluminescence method
EP0327588B1 (en) High sensitivity optical imaging apparatus
US7585624B2 (en) Detection of the energy of photons from biological assays
JP2001516028A (en) Scintillation proximity test
AU2002330613A1 (en) Detection of the energy of photons from biological assays
EP0937238B1 (en) Method for assay analysis
AU1364300A (en) Quantitative determination of analytes in a heterogeneous system
Berthold et al. Luminometer design and low light detection
JPS61217745A (en) Image immunity test detector and method
JP2024506285A (en) Sensitive chemiluminescence detection system and method
US20030143532A1 (en) Method for producing biochemical analysis data and apparatus used therefor
Hooper Ultra-sensitive quantitative imaging of luminescent immunoassays and cellular assays using image intensifier and CCD detectors
JP2728796B2 (en) Chemiluminescence measuring method and measuring device
AU773541B2 (en) A digital imaging system for assays in well plates, gels and blots

Legal Events

Date Code Title Description
AS Assignment

Owner name: DX COMPANY, LTD., TEXAS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:LEABACK, DAVID H.;REEL/FRAME:006136/0777

Effective date: 19850723

STCF Information on status: patent grant

Free format text: PATENTED CASE

AS Assignment

Owner name: INTERNATIONAL MUREX TECHNOLOGIES CORPORATION, GEOR

Free format text: SECURITY INTEREST;ASSIGNOR:MUREX CORPORATION;REEL/FRAME:006496/0413

Effective date: 19930319

CC Certificate of correction
AS Assignment

Owner name: MUREX CORPORATION, GEORGIA

Free format text: EXCHANGE AND ASSIGNMENT OF INTERESTS;ASSIGNOR:DX COMPANY LTD.;REEL/FRAME:006737/0871

Effective date: 19860425

CC Certificate of correction
FEPP Fee payment procedure

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

FPAY Fee payment

Year of fee payment: 4

FEPP Fee payment procedure

Free format text: PAYER NUMBER DE-ASSIGNED (ORIGINAL EVENT CODE: RMPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

FPAY Fee payment

Year of fee payment: 8

FPAY Fee payment

Year of fee payment: 12